Physiology Summary PDF

Dr.Ahmad Al-Qawasmi physiology summary ‫للتسجيل بالمراجعة‬ Details ⬇️➡️ https://t.me/+5phjc9oVBchlNTJk Introduction to Physiology: ❖ System level Systems emerge to meet the needs of the body such as the need for suppl...

Dr.Ahmad Al-Qawasmi physiology summary ‫للتسجيل بالمراجعة‬ Details ⬇️➡️ https://t.me/+5phjc9oVBchlNTJk Introduction to Physiology: ❖ System level Systems emerge to meet the needs of the body such as the need for supplying the cells with nutrients and to get rid of the wastes A system consists of related organs with a common function ➔ Each system works for a certain function, but all of them work for keeping the internal environment almost constant (Homeostatic function) ❖ Homeostasis It is a condition of equilibrium (balance) in the internal environment of the body, where it is maintained at an almost constant level Homeostasis is dynamic not static, that means that the body has a normal range of values for each variable (with narrow variation) A variable is a condition in the internal environment of the body, such as blood pressure (BP), blood glucose level (BGL), body temperature, PH of blood, concentration of {CO2, O2, Na+, K+, Ca+2} ❖ Feedback System If there is a disturbance (abnormal changes) in the homeostasis ➔ Feedback system works to restore the homeostasis (balance) It keeps the internal environment constant Feedback system has three Basic components: 1. Receptors: Body structures that monitor changes in a controlled condition Sends input to the control center Example: Nerve ending of the skin in response to temperature change 2. Control center: Brain Sets the range of values to be maintained Evaluates input received from receptors and generates output command Example: Brain acts as a control center by receiving nerve impulses from skin temperature receptors 3. Effectors: Receives output from the control center Produces a response or effect that changes the controlled condition Found in nearly every organ or tissue Example: Body temperature drops skin receptors sense drop the brain sends impulse to effector (skeletal muscles) muscles contract rapidly causing shivering which generates heat Note: Input & Output can be ➔ Nerve impulses or Hormones Feedback system is divided into Negative & Positive systems: Positive Feedback systems Strengthen or reinforce a change in a controlled condition Examples: Normal childbirth, Blood Loss So the response is in the same direction as the stimulus Negative Feedback systems Reverses a change in a controlled condition Examples: PH changes, Regulation of calcium levels, Regulation of blood pressure stimulus and response opposite each other (if one of them increases the other one decreases) Notes: ✓ In the Ca+2 regulation the effector is parathyroid gland ✓ In the blood pressure regulation, the receptors are called Baro receptors ✓ Blood pressure is the force exerted by blood as it presses against the walls of the blood vessels (the resistance to blood flow) ✓ Vasodilation: decrease in BP (so decrease in the resistance to blood flow) ✓ Vasoconstriction: increase in BP (so increase in the resistance)  ❖ Generalized Body Cell: The outer boundary of the cell ➔ Plasma membrane ➔ It separates the internal environment of the cell from the external environment It is a selective barrier Membranes are made from a lipid bilayer that contains proteins Cells have also membranes in the cytosol ➔ Surround the organelles ➔ Lead to compartmentalization and separate each organelle from the others and this help in controlling cell functions ER (Endoplasmic Reticulum) is a membrane bound organelle & it is divided into rough endoplasmic reticulum (RER) and smooth endoplasmic reticulum (SER) RER has Ribosome on its surface Ribosomes is the apparatus responsible for protein synthesis Lysosomes are membrane bound organelles & they contain digestive enzymes to break materials Mitochondria are double membranous (inner and outer membranes) Contain high concentration of protons (H+) in the intramembranous space ➔ due to the presence of ETC (electron transport chain) The last complex (5th) in the ETC is ATP synthase ➔ use the concentration gradient of H+ to produce ATP Cytoskeleton is composed of proteins (microtubules, actin filaments and intermediate filaments) They determine the shape of the cell (shape serves the function) ✓ Muscle cells are elongated ➔ increase the efficiency of contraction ✓ Red blood cells are biconcave disks ➔ to bind oxygen and diffuse more efficiently ✓ In neurons we have dendrites which increase surface area to receive more signals Help in transporting material and vesicles inside the cells (mainly microtubules) Microtubules make the mitotic spindles which help in cell division Microtubules make Cilia which project from the surface of the cell & cilia are responsible for moving mucus Actin filaments ➔ form pseudopods help in moving the cell & participate in muscles contraction Structure of the Membrane: It is composed from a lipid bilayer ➔ made up of phospholipids, cholesterol and glycolipids Phospholipids have a polar head (hydrophilic) and 2 hydrocarbon (hydrophobic) tails Cholesterol ➔ decrease membrane fluidity (decrease the movement of the membrane and increase its stability) The membrane is not static (Dynamic) and it is constantly moving It contains many proteins: 1. Integral proteins: Extend through the lipid bilayer & usually act as channels and carriers 2. Peripheral proteins: Attached to the inner or outer surface of the membrane, do not extend through it & they are involved in maintaining cell shape, cell motility and can be enzymes Glycoproteins they are membrane proteins with a carbohydrate group (protrudes to the ECF) Membrane proteins can act as channels, carriers, linkers, enzymes and cell identity markers: Channels: ✓ Move ions across the membrane down their concentration gradient, they can be linked to receptors ✓ Aquaporins: They are channels that move water across a membrane Carriers: ✓ Transport molecules across the membrane by having conformational changes  ✓ They can transport molecules down their concentration gradient (facilitated diffusion) or against concentration gradient (active transport) Linkers: ✓ They are the junction between cells that connect them together and allow them to communicate ✓ There are 3 types of linkers: ▪ Tight junctions ▪ Gap junctions (pores between cells, allow them to exchange materials and communicate) ▪ Desmosomes (Adhering junctions) (They help cells to keep in contact next to each other and they are attached to cytoskeleton) Cell identity markers: ✓ Each cell has unique glycoproteins, which help in identifying the cell ❖ Membrane Permeability: Selective permeability means that the membrane is either permeable to certain molecule or impermeable It is permeable to lipid soluble substances (such as O2, CO2, water and steroids) Or impermeable to some molecules (such as ions and glucose) & they are transported across the membrane by transmembrane proteins (channels and transporters) There are 2 types of transporting the molecules across a membrane ➔ Passive & Active Transport ❖ Passive Transport: Substances move across cell membranes without the input of any energy ➔ from higher concentration to lower concentration = Down Concentration Gradient = Downhill what drives it to move across the membrane? The kinetic energy of the molecules Diffusion rate (J): There are 5 factors on which diffusion depends: Directly proportional: Concentration Gradient, surface area, solubility in lipid inversely proportional: square root of molar mass, thickness of membrane Also, diffusion depends on temperature P ➔ Permeability in lipid Fick’s law of diffusion: (C2-C1) ➔ Concentration J = P (C2 – C1) × S gradient ΔC ➔ Concentration gradient J = DA × (ΔC/ ΔX) A ➔ Area S ➔ Surface area. ΔX ➔Thickness of the membrane D ➔ Diffusion coefficient (depends on the solubility in lipids, molecular weight). Passive Transport is divided into: Simple diffusion: The molecules move through the Lipid Bilayer down there concentration gradient Which molecules cross the membrane using simple diffusion?? Lipid soluble substances Examples: H2O, Gasses ( O2 ,CO2 ,N2), Ammonia, Steroids, Small alcohols, Glycerol, Fat-soluble vitamins (Vitamin A , D, E ,K) Facilitated diffusion: The molecules move across the membrane using transmembrane proteins(channels and carriers) down there concentration gradient Which molecules cross the membrane using facilitated diffusion?? Lipid insoluble substances It has 2 types according to the transmembrane protein used:  Channel-Mediated Facilitated Diffusion (for ions like K+, Na+)  Carrier-Mediated Facilitated Difusion (for larger molecules like glucose) We can call Diffusion using Channels either Facilitated or simple diffusion by channels  Some channels have a gate, that can be opened and closed by: Change in voltage (Voltage-gated) Change in the concentration of a particular Substance (Chemically-gated) Facilitated diffusion (by carriers) has a limit and a maximum of diffusion rate (T max or V max) ➔ it is called saturable, Because it depends on the number of available carriers and binding sites In the diffusion by channels there is no limit of the rate (no Vmax) Osmosis: The net movement of water through a selectively permeable membrane It moves from High concentration of water to low concentration of water (or low concentration of solutes to high concentration of solutes) Water can pass through plasma membrane through lipid bilayer or through aquaporins, which are channels specific to water Solution pressures: ✓ Hydrostatic pressure: ▪ Is the pressure exerted by a stationary fluidic part of the solution on an object (semi permeable membrane in case of Osmosis) ✓ Osmotic pressure: ▪ It is a pulling pressure that measures the tendency of a solution to pull the water into it, because the concentration of non-penetrating solutes (water move toward the higher conc. of solution) ▪ So it Depends mainly on Osmolarity Equilibrium It is a state when the movement of water under osmotic pressure equals the movement of water under hydrostatic pressure [Net hydrostatic (Solution) pressure of a solution = Zero] Net hydrostatic pressure = hydrostatic pressure – osmotic pressure Relation between osmolarity and molarity Osmolarity or mOsm/L = The concentration of particles (active substances) per liter solution Molarity or mM/L = index of concentration of molecules per liter solution If Molarity is (n) so Osmolarity is (i x n), i ➔ is the number of active particles Van’t Hoffs equation: ✓ 𝝅 = 𝒊𝒏𝑹𝑻 = C𝑹𝑻 Content of the body fluids: In the normal body the ECF & ICF have the same osmolarity (approximately 280-300 mOsm/L) What happens a red blood cell when putting it in ✓ Isotonic solution: It remains normal (the net movement of water is zero) ✓ Hypotonic solution: The water will move toward the higher osmolarity (high solute concentration), so it will enter the cell ➔ causing Swelling ✓ Hypertonic solution: The water will get out from the cells ➔ causing Shrinking  ❖ Active Transport: It requires input of energy (uses energy) Solutes are transported against the concentration gradient (from the lower conc. to the higher conc.) Such as: Sodium-potassium pump Na/K pump is an electrogenic pump ➔ because it causes a separation of charges (Difference in charges inside and outside the cell ➔ voltage across the membrane) Active Transport is divided into: Primary Active Transport: ▪ Molecules are “pumped” against a concentration gradient at the expense of energy ▪ direct use of energy (Direct use of ATP) ▪ driven by pumps such as: Potassium sodium pumps /calcium pumps/ hydrogen pumps Secondary Active Transport: ▪ Transport is driven by the energy stored in the concentration gradient of another molecule (such as Na+), indirect use of energy ▪ It has 2 types : Antiporter (Counter transport): Transport 2 substances in 2 directions (opposite to each other) ✓ Examples: Na+ + Ca2+ / Na+ + H+ Symporter (Co-transport): Transport 2 substances in 1 direction (the same direction) ✓ Examples: Na+ + Glucose / Na+ + Amino Acid The primary & secondary active transport are saturable (They are rate limited by Vmax of the transporters) Up to 90% of the cell energy expended for active transport Transport In Vesicles: Exocytosis ➔ vesicles fuse with the plasma membrane, releasing their contents into the extracellular fluid Endocytosis ➔ Materials move into a cell in a vesicle formed from the plasma membrane There are 3 types of endocytosis: Phagocytosis: cell uses pseudopods to capture the molecules and take it into the cell (to be digested by the Lysosomes) Pinocytosis (bulk-phase endocytosis): it is mainly used for fluids, and it may use pseudopods Receptor mediated endocytosis: it is almost specific to a certain substance, and it may use pseudopods Transcytosis ➔ It is a combination of Endocytosis and Exocytosis at the same time ❖ Control of membrane proteins activities ligand binds to its receptor (which is a type of proteins) and the receptor changes protein activities. ligands are signal molecules that bind to a specific receptor Receptors control ➔ Ion Channels, Enzymes, Vesicular Transport ❖ Receptors & Channels: What links the receptor with the channel? G-proteins When a ligand binds the receptor ➔ G-protein activation ➔ which activates the channels (that means opening the channels and change membrane permeability) G-Proteins have 3 subunits ➔ Alpa, Beta and Gamma (Alpha is the most important one) G-proteins are protein complexes that link a receptor to its effector (channel, enzyme,…) ❖ Receptors & Activation of Enzymes: Also some receptors are linked to enzymes through G-proteins Examples: 1. Gs Activates Adenylyl cyclase [Converts ATP molecule into cAMP (cyclic AMP)] 2. Gi Inhibits Adenylyl cyclase 3. Gq Activates phospholipase C [Converts ( PIP2 ) into (IP3 & DG )] ❖ Receptors & Vesicular Transport: Regulation of endocytosis ➔ In receptor mediated endocytosis, receptor can activate endocytic processes by stimulating the formation of the vesicle Regulation of Exocytosis ➔ It is used is the synaptic transmission between two neurons  ❖ Transport of ions across the plasma membrane The the plasma membrane separates two different compartments of different compositions Cytosol has high concentration of proteins and potassium ions K+ Extracellular fluid has high concentration of sodium ions Na+ and chloride ions Cl- Electrical properties of Plasma membrane in excitable cells is similar to an electrical device called capacitor Generally, the membrane has a low permeability for ions, but the permeability of a certain ion can increase by increasing the number of active channels for this ion ( active channels ➔ permeability for this ion) If the membrane is highly permeable for one ion, it will move down its concentration gradient across the membrane, that create Membrane potential If the membrane is highly permeable to potassium ions K + only (and has no permeability for Na+ and Cl-), then K+ will move down its conc. gradient from inside to outside through active k + channels, that creates electrical potential due to the accumulation of K+ outside (positive charge will be on the outer surface and negative on the inner) If the membrane is highly permeable to sodium ions Na+ only, then it will move down conc. gradient from outside to inside through active Na + channels, that creates electrical potential due to the accumulation of Na+ inside (negative charge will be on the outer surface and positive on the inner) Diffusion stops because of electrochemical equilibrium (there is 2 energies act on ions) ✓ Chemical energy created by concentration gradient across the membrane that pushes ions to move from high concentration to low concentration ✓ Electrical energy created by voltage gradient (potential/charges) that was originally generated by movement of ions, this energy pushes ion in the opposite direction due to charge repulsion At equilibrium ➔ The chemical concentration isn’t equal across the membrane instead the Electrochemical gradient equals Zero (net diffusion of ions = 0) We can calculate the potential generated by the movement of one ion across the membrane (Equilibrium potential of an ion) by Nernest Equation Nernest Equation Goldman-Hodgkin-Katz equation The cord conductance equation g ➔ Conductance P : membrane permeability to that ion Vm ➔ Voltage (potential) of the membrane i : conc. of the ion inside E ➔ Equilibrium potential for the ion o : conc. of the ion outside Calculate the potential generated Calculate the potential generated Calculate the potential generated across a membrane that is Permeable across a membrane that is across a membrane that is for one ion only Permeable for more than one ion Permeable for more than one ion The conc. of the Cl- inside the cell above Conductance is similar to permeability, the outside (because it’s valance is -1) BUT permeability describes the movement of particles and If the membrane has a high permeable conductance describes the movement of charged ions to one ion (ex:Na+) and very low ion to the other ions (K+, Cl-) the the It is the reciprocal ‫ مقلوب‬of the membrane potential will be close to the resistance (R) ➔ g = 1 / R equilibrium potential of that ion (Na+) Ohm’s law: (R = Delta V / I ), So (g = I / Delta V )  ❖ Resting potential It is the potential of a membrane before the arrival of a stimulus (not active) ➔ It results from the original permeability of the membrane Resting potential differs between different membranes Because the permeability for each ion is different between membranes ➔ So, the main effect on the resting potential is due to permeability The main factors involved in establishing resting potential: 1. Activity of K+ channels It is the most influential factor Because the activity of K+ channels is very high (high permeability) 2. Activity of Na+ channels It has a low effect Because the small number of Na+ channels (low permeability) K & Na+ together contribute to (-86 mv) ➔It is closer to the potential of (K+) because it has much higher + permeability than Na+ (The permeability of K+ is about 100 times more than that in sodium) 3. Contribution of Na+/K pump It contributes by -4 mv because it pumps 3Na+ outside and 2k+ inside So, all together contributes by -90 mv (in neurons) Notes: ✓ If the activity of K+ channels (K+ permeability) decreased the potential will be less negative ✓ If the resting potential of a membranes equals the equilibrium potential of an ion the activation of more channels for this ion will not change the resting potential ❖ PATCH CLAMP It is a technique that is used to measure the current that can pass through the membrane at fixed voltage point In this technique we are measuring the current across a part of the membrane, if there is a high number of active channels of an ion, there will be a high current of this ion (because current depends on permeability and conductance) ❖ Action & Graded potential Polarization: It is the separation of opposite charges across the membrane (at resting potential when there isn’t any stimulus), results from the low permeability to Na+ and much higher permeability to K+ Depolarization: Removing polarization, occurs When a stimulus arrives Na+ channels are activated and leads to less separation of charges ➔ taking the potential to a less negative value than resting potential If membrane potential reached the Threshold potential ➔ action potential is generated and a very fast and sudden activation of sodium channels is achieved ✓ At threshold ➔ Activation of Na+ channels (Fast) & activation of K+ channels (slower rate) This rapid activation of voltage gated Na+ channels is called Rising Phase (also called firing stage), where the potential continues to decrease (less negative) When the membrane potential reaches zero and also a positive value up to the peak (the highest positive value), then this stage is called Overshoot Repolarization (it is also called Falling phase): Returning to polarization ➔ going toward resting potential, results from the close of almost all Na+ channels and the gradual activation of K+ channels When the potential reaches the peak ➔ that leads to a fast inactivation (closing) of Na+ channels and activation of K+ channels (gradual) and it continues until resting potential is reached (returned) When reached there will be a very fast inactivation (closing) of K+ channels Hyperpolarization: More polarization, and so more separation of charges, and more negative potential than resting potential, results from the more activation of K+ channels after resting potential It is also called Positive after potential / After hyperpolarization / Undershoot Notes: Chloride participation in resting potential is neglected Voltage gated channels for both Na+ & K+ are activated when reaching threshold Action potential is divided into phases: ✓ Phase 1: Resting potential (polarization) ✓ Phase 2: Depolarization (up to threshold potential) ✓ Phase 3: Rising phase (firing stage), in this phase we have the highest Na+ channels activity ✓ Phase 4: Repolarization (falling phase), in this phase we have the highest K+ channels activity ✓ Phase 5: Hyperpolarization (undershoot) Graded potential is any change in resting potential (more or less negative) without reaching threshold Excitable cell is a cell that generates action potential (neurons & Muscle cells) Ionic current it is the movement of charged particles (mainly positive), for example when there is a depolarized region near to a resting region ➔ positive particles will move toward the negative region, leads to depolarization In a resting membrane there is a high resistance to ionic current because most ionic channels are closed, when opened the resistance decreases We can find Na+ channels in 3 conformation (states): Opened: During the rising phase (firing stage) almost all sodium channels are opened Closed and capable to opening: During resting potential [activation gate is closed] Closed and not capable to opening: During all the falling phase, when Na+ channels are closed after reaching the peak (positive values of potential) [inactivation gate is closed] When the potential return to resting potential or more negative, the closed and not capable to open Na+ channels are transformed into closed and capable to open ❖ Refractory periods It is a period at which if the membrane is stimulated it wouldn’t generate a new action potential Absolute refractory period Relative refractory period It starts from the firing stage to the end of first third of From the falling phase until the resting potential is reached falling phase The cell will not respond to a usual stimulus, but if there is a The cell will not respond to any stimulus even if it is a suprathreshold (stronger) stimulus ➔ may activate the stronger stimulus closed channels that are not capable for opening by normal stimulation Sodium channels are closed and not capable to open, when Sodium channels are opened in this state we get out of the relative refractory period (reach resting potential) the channels are closed but capable to ope  Importance of refractory periods in conduction ➔ The refractory periods ensure the one-way (unidirectional) propagation of action potential from the axon hillock toward the terminals only ❖ Involvement of other ions in action conductive tissue: is an excitable tissue (it is not neither muscular nor nervous tissue) in the heart ➔ can generate an automatic action potential (when an action potential finishes, a new action potential will be generated due to sodium leakage) In the SA (sinoatrial) node ➔ action potential is generated every 0.8 seconds (75 action potential per minute) which is a pacemaker of the heart In the cardiac muscle the action potential is called action potential in plateau ➔ there is a very fast depolarization ➔ slight repolarization occurs ➔ then repolarization stops for a while ➔ so we have a longer period of action potential in cardiac muscle ❖ Neural Structure The main parts of the Neural cell: ❖ Cell body (the soma): contains most of the organelles of any cell like the nucleus, endoplasmic reticulum (ER), mitochondria, nissl bodies and granules which are the site of protein synthesis in neurons they’re synonymous to ribosomes Neurons lack the centriole because neurons don’t divide nor regenerate ❖ Axon hillock (trigger zone): It is the junction between the cell body and axon, which motor neurons generate action potential at it It has the largest number (highest density) of voltage gated sodium channels & the lowest threshold for the action potential ➔ Its the site where action potential mainly occurs ❖ Dendrites: Tree-like shaped structures with a small diameter that collect information from a large area. It’s rare for the action potential to occur in the dendrites, because they lack voltage gated sodium channels, almost nonexistent, which makes their threshold very high & the high resistance for Action potential conduction due to its small diameter ❖ Axon: At the end of the axon there are axon terminals (they are also called knobs or buttons) that contain neurotransmitters that are released once the action potential (nerve impulse) reaches the terminals There are 2 types of axons according to the presence of myelin: Myelinated ➔ Action potential is transported from a node of Ranvier to another in salutatory (jumping) way which is faster Non-myelinated ➔ Action potential is Transported along the axon in continuous way which is slower ❖ Supportive Cells (Neuroglia): They are cells in the Nervous system, have several functions, such as: 1) Maintenance of neural environment, by keeping very low concentration of K+,to have optimal activity of membrane 2) Destroy neurotransmitters 3) Synthesize and release neurotrophic factors ,maintain the survival and protection of neurons 4) provide nutrition 5) Other specialized supportive cells are responsible for myelination of axons (such as Schwan cells) Schwan cells: Specialized supportive cells in the peripheral nervous system, they around the axon and secrete myelin sheath, and the gaps in the myelin sheath between these cells are called Nodes of Ranvier Myelin sheath: ✓ It is the sheath around some axons ➔ Help electrical impulses to transmit quickly along nerve cells ✓ It is composed of sphingolipids, it has a white color (in the CNS myelin is called white matter) Synapse: The connection between the terminal of first neuron and the membrane of the second one  Now let’s talk about the 2 types of action potential propagation (conduction): Continuous conduction: (Slow) ▪ Action potential moves along the axon of the unmyelinated neurons ▪ Action potential is propagated between adjacent regions by the ionic current, this current occurs in both surfaces of the plasma membrane but the current in the inner surface is more important Salutatory conduction: (Fast) ▪ Action potential moves from Ranvier node to another in the myelinated neurons by the internal (ionic) current What determines the velocity of conduction?! 1) Myelination (Myelinated axons conduct action potential faster because we skip big parts of the axon) 2) Diameter of nerve fibers (axons), larger fiber (lower resistance) ➔ higher velocity ❖ Transmission of action potential between neurons Presynaptic membrane is the membrane of the synaptic knob How action potential is propagated from a neuron to another?! 1) When the impulse from the presynaptic neuron reaches the synaptic knob, this will cause activation of voltage dependent Ca++ channels (voltage-gated channels) ➔ Ca+2 diffuse into the synaptic knob 2) Increase in Ca++ concentration inside axon terminal ➔ reducing the electrical repulsion (between the negatively charged membrane of the vesicle and the negatively charged presynaptic membrane) ➔ trigger the release of neurotransmitter from vesicles into synaptic cleft by a process of exocytosis 3) Once neurotransmitters are released it binds to its receptor on the membrane of the second neurons ➔ induce changes in the postsynaptic membrane (decrease or increase in the membrane potential) EPSPs (Excitatory Post Synaptic Potentials) ➔ It is the decrease in postsynaptic potential (doesn’t reach threshold) after the binding of the neurotransmitter to its receptor, induced by: ✓ Activation of a few Na+ channels IPSPs (Inhibitory Post Synaptic Potentials) ➔ It is the increase in postsynaptic potential after the binding of the neurotransmitter to its receptor, induced by: ✓ K+ channels activation (Hyperpolarization) ✓ Sometimes activating Cl- channels (it will move inward the postsynaptic neuron), the activation of chloride channels is inhibitory but it doesn’t induce hyperpolarization The channels on the postsynaptic membrane are chemical gated channels When more than one EPSP affect the postsynaptic neuron, each one of them generates a small depolarization (doesn’t reach threshold) but the summation of them together will reach threshold and generate action potential, We have 2 types of summation: Spatial summation Temporal summation 2 or more stimulation from 2 or more presynaptic neuron 1 presynaptic neuron acts on acts on the same site of the postsynaptic membrane 1 or more postsynaptic neuron Several stimulation act at the same time (simultaneously) Several stimulation act at different time  If the summation is between: ✓ 2 or more EPSPs ➔ eliciting more depolarization ✓ 2 or more IPSPs ➔ eliciting more hyperpolarization ✓ EPSPs & IPSPs ➔ results in cancellation of potentials After inducing the appropriate response at the postsynaptic membrane, the transmitter should be removed by: Some types of transmitters are transported back into synaptic cleft without inactivation Some transmitters are inactivated by postsynaptic membrane bound enzymes (Such as acetylcholine esterase ➔ destroys acetylcholine (Ach) into acetyl + choline) ❖ Synaptic organizations Some presynaptic neurons can attach to only one postsynaptic neuron, and others can attach to more than one, also sometimes many presynaptic neurons are attached to one postsynaptic neuron Neural network in our bodies has 2 dominant structures: Convergence: It is the synapsing of many axonal terminals from different neurons to one neural cell body (many presynaptic ➔ one postsynaptic) ➔ Many Inputs Divergence: It is the synapsing of the terminals (branched from the same neuron) to different neurons (one presynaptic ➔ many postsynaptic) ➔ Many Outputs Reverberating circuit Parallel after-discharge circuit ❖ Action Potential Recording ✓ Monophasic action potential: We place one electrode outside and one electrode inside the cell during any action potential phase The recording would be either positive or negative but not both It is called monophasic because it records the potential difference between inside and outside in the same region so in the same phase (resting, depolarization,…) ✓ Biphasic action potential: We place both electrodes outside but in 2 different regions It is called biphasic because the recording is between 2 regions and so they could be in 2 different phases If there is action potential ➔ the 2 adjacent regions will be different, so we record 2 waves ( depolarization wave and then repolarization wave) ✓ Compound action potentials: The nerve holds many fibers (axons), these axons differ in their conduction velocity for action potentials due to their properties (myelination, diameter) Compound action potentials: It is the sum of all recorded action potentials generated by all nerve fibers at a certain point , by sensing the voltage difference between zero and the voltage of the axon It is done by placing one electrode at a source of voltage = 0 (high resistance source) and the other one at a point on the nerve We measure the potential at many points on the nerve At each point there will be a different wave recording (potential) Each wave represents the integrity of fibers and their different conduction velocity Alpha Fibers conduct AP Faster than Beta Fibers  ‫تفاصيل الدورة المكثفة )المراجعة(‪:‬‬ ‫شرح المادة كاملة في أقل من ‪ 7‬ساعات‬ ‫ ‬ ‫الشرح والمخلص شاملين كل شي باذن هللا‬ ‫ ‬ ‫الملخصات موجودة في مجموع التيليجرام باألسفل‬ ‫ ‬ ‫سعر المراجعة‪ :‬خمسة دنانير فقط‬ ‫ ‬ ‫كيفية التسجيل‪:‬‬ ‫‪ )1‬الدفع اما عن طريق زين كاش للرقم ‪ 0792870752‬أو بيجيك مندوب من الموقع للدفع‬ ‫‪ )2‬عمل حساب على موقع ‪Medlearn-jo.com‬‬ ‫‪ )3‬تعئبة الفوم التالي‬ ‫‪https://forms.gle/n92jYxwBB8XwnpAd9‬‬ ‫عشان نضيف لك المراجعة ان شاء هللا🔥🔥‬ ‫‪Medicine with Dr.Ahmad‬‬ ‫‪medicine_with_dr.ahmad‬‬ ‫‪https://t.me/+5phjc9oVBchlNTJk‬‬ ‫‪https://chat.whatsapp.com/FqYqxIz4X38J1Z7vW3gkPE‬‬  ❖ Important definitions Signaling: cell-cell communication via signals Signaling transduction: process of converting extracellular signals into intracellular response without the physical ingress of the molecule to the cell LIGAND: the signaling molecule (Such as hormones) RECEPTOR: specific proteins that bind to specific ligands, they transmit signals to intracellular targets ❖ Components involved in signaling transduction: 1. Ligand 2. Receptors: 3. Intracellular signaling proteins (mediatory proteins): It includes the following: Intermediary proteins / Enzymes / Second messenger / Target protein / Inactivating proteins The final response happens to the target protein, The target could be: A metabolic enzyme by activating or inactivating it ➔ altering the metabolism in the cell A gene regulatory protein ➔ which alters gene expression A cytoskeletal protein ➔ can transport an object from inside to outside the cell in variety of processes such as, exocytosis , cell division and altering cell shape and movement ❖ Importance of signaling: Signaling is responsible for how cells can respond to their environment and how they can differentiate 1) Allows cells to respond to environmental changes such as : changes in temperature, in oxygen availability 2) Graded signals induce cells to differentiate into different types of cells 3) Combined signals can cause differentiation 4) Signals can be inhibitory ➔ signals that are inhibitory for a certain cell can stop or slow many mechanisms 5) Different signals can integrate to help the cell to adjust to external changes or to change with time Not all of the receptor needs to be bound to induce a response ❖ CHARCTARASTICS OF SIGNALS: Signals can act locally or at a distance Locally = At a short Distance or at the same secreting cell ligands, in this case the ligands are called local mediators At a distance = Some ligands such as hormones secreted from glands are transported via blood (circulation) into a distant target cell Responses can be fast or slow depending on the mechanism induced to make changes the responding cell Fast response: Slow response: ✓ In the cytoplasm ✓ In the nucleus ✓ Takes seconds to minutes ✓ Minutes to hours and days ✓ Such as the activation of a cytosolic enzyme ✓ Such as altering gene expression Signals are amplified ➔ It means that: 1 ligand molecule causes more than one second messenger, and each 2nd messenger can act on many targets, and so on… ❖ TYPES OF SIGNALING: 1. Contact-dependent-via proteins in the plasma membrane: Between the adjacent cells (they are connected together by intermediate receptor)  2. Via secreted signals: Autocrine: via growth factors, the cell that releases the ligand is the target, it is a type of feedback (Mostly negative feedback ➔ to maintain Homeostasis) Paracrine: via neurotransmitters and cytokines, action on adjacent target cells Endocrine: via hormones , action on distant target cells ➔ so circulate in the blood Synaptic: via neurotransmitters, action on post synaptic cell in response to electrical stimuli Note: (Autocrine and Paracrine ➔ local) / (Endocrine ➔ circulating) ❖ Types of signaling ligands: 1) Ligands that bind to cell-surface receptors: ▪ Neurotransmitters (NT) Such as norepinephrine, histamine ➔ charged, polar so can't cross the membrane ▪ Peptide hormones (P) Such as insulin ➔ can't cross membrane because they are large molecules ▪ Growth factors (GF) Such as NGF, EGF, PDGF ➔ charged molecules ▪ Lipophilic signaling molecules Such as prostaglandins ➔ they aren’t lipid soluble (Charged) 2) Ligands that bind to intracellular receptors: Lipid soluble hormones that diffuse across the plasma membrane and interact with receptors in the cytosol or nucleus (such as steroids, thyroxine, retinoic acid, nitric oxide) ❖ Chemical classes of hormones: LIPID SOULABLE HORMONES: WATER SOLUBLE HORMONES: Non-polar (Water insoluble) Polar (Water soluble) They use transport proteins in plasma & They can easily cross the Circulate freely in the plasma (without transport proteins) & They plasma membrane and bind to their targets can’t cross plasma membrane Steroids: Lipids derived from cholesterol (Testosterone, Amines: hormones derived from tyrosine and tryptophan Estradiol, Cortisol, Progesterone) Polypeptides and proteins: Thyroid: Amine but lipid soluble such as T4 (thyroxine Polypeptides: chains of < 100 amino acid length (example: [tetraiodothyronine]) ADH ) Protein hormones: polypeptide chains > 100 amino acid (example: growth hormones) Nitric oxide (NO) : Due to its gaseous nature, it easily Eicosanoid (prostaglandins): penetrates the plasma membrane local mediators derived from arachidonic acid (20 carbon 4 double bonds),in physiological level they are charged molecules so the can’t enter inside the cell Glycoproteins: Long polypeptides >100 bound to 1 or more carbohydrate (CHO) groups ➔ They have alpha and beta subunits (alpha is common and beta is specific) Examples: FSH,LH,TSH and hCG (human chorionic gonadotropin) ❖ Prohormones and Prehormones: Hormones are synthesized in the Nucleus ➔ then packaged in the ER ➔ then into the Golgi apparatus for post- translational modification, packaged ➔ then released by exocytosis Prohormone: it is precursor = a longe chained polypeptide that is cut and spliced together to make the hormone Preprohormones: Larger precursor molecule that prohormones are derived from Prehormone: Molecules secreted by endocrine glands that are inactive until changed into Hormones by target cells ➔ Such as: T4 converted to T3 (tri-iodothyronin)  )‫في هذا الجدول لخصتلكم كل الهرمونات المطلوبة منكم (ركز على الغامقين‬ Hormone Type The Hormone Mode of secretion Amino Acids derivatives Epinephrine (Adrenaline), Norepinephrine Endocrine (Amines) T4, T3 (Thyroid) [Lipo-philic] Dopamine ------------ [All the above are Tyrosine derivatives] Histamine Paracrine Steroid hormones Estrogens, Progesterone, Androgens, Testosterone (sex hormones) and corticosteroids Endocrine Cortisol, Estradiol, Aldosterone, Androgens Calcitriol (1,25-Dihydroxycholecalciferol) ------------ Peptide and protein TRH, GnRH, CRH, GHRH, Somatostatin, ACTH, TSH, FSH, LH, hormones PRL, GH, Posterior pituitary, Oxytocin, ADH, Calcitonin, Insulin, Glucagon, Somatostatin, Somatomedin C (IGF-I), PTH, ----------- HCG, HCS, or HPL, Renin, ANP, Gastrin, CCK, Secretin, GIP, Somatostatin, Leptin, growth hormones Thyroxine [Tyrosine derivatives] Antidiuretic hormone (vasopressin) Hypothalamic Hormones (releasing factors) Anterior Pituitary hormones Endocrine Eicosanoid (Arachidonic acid Prostaglandins Paracrine derivatives) Glycoproteins FSH, LH, TSH and hCG (human chorionic gonadotropin) ----------- ❖ Hormone Activity: Hormones only affect specific target tissues with specific receptors Receptors are dynamic and can be either broken down or synthesized in the membrane Different density for hormones gives different response Effects of Hormones in tissue response Priming effect (Up regulation): ▪ Increase the number of receptors formed on target cells in response to particular Hormone ▪ Greater response by the target cell Desensitization (Down regulation): ▪ Decrease in number of receptors on target cell ▪ Caused by the prolonged exposure to high concentration of hormone (especially polypeptide) so the subsequent exposure to the same concentration of ahormone produces less response ▪ Example: Insulin in adipose tissue (Diabetes 2) ▪ Pulsatile (not continuous) secretion may prevent downregulation ❖ Effects of hormone concentration on tissue response Hormone concentration in blood depends on the rate of secretion & Half life Half-life is the time required for the blood hormone concentration to be reduced to half the reference level (Normal Physiological level) ➔ It may be minutes to days Normal tissue response is produced only when Hormone concentration is within physiological range Affinity of receptors to ligand (Kd) affects the half life  ❖ Mechanism of hormone action: Hormones of same chemical class have similar mechanisms of action, similarities include: 1) location of cellular receptor protein (depends on the chemical nature of the hormone ). 2) events that occur in the target cells Hormone exhibit: Affinity: depends on the chemical structure, strength and number of bonds in hormone Saturation (low capacity of receptors): The ratio and number of bound hormones to receptor Some hormones need high saturation to make response, others need just low The response to a hormone depends on the type of hormone a, its receptor and the target cell Lipid-soluble hormones bind to Intracellular receptors (inside the target cell), and the receptor may be in the cytosol or in the nucleus (It can also bind to the receptors on the PM) Water-soluble binds to receptors on the plasma membrane ➔ activates second messenger ➔ amplification of original response Responsiveness of target cell to a receptor depends on Concentration of hormone & Abundance of target cell receptor Ligand ➔ A small molecule that binds specifically to a larger one (receptor) Receptors ➔ Receptor determines response (when there is no receptor ➔ there is no response) Receptors have characteristic properties, such as: ✓ Specificity: It is a description of how favorable the binding of the ligand for the receptor is compared with its possible binding to other types of receptors that may also be present ✓ Affinity: It is how strong the binding is between receptor and certain ligand (can be judged by Kassociation or Kdissociation and ∆Go) ▪ High affinity refers to very strong binding (large negative ∆Go and a very small Kd) And the concentration needed for the ligand to bind to the receptor is small ▪ Dissociation constant: The concentration of a ligand that s required to occupy 50% of the receptors Receptors can be: Membrane receptors They are integral transmembrane proteins Membrane Glycoprotein or sometimes Lipoproteins The only option for the water-soluble ligand Intracellular receptors Can be in Cytosol (cytosolic) or Nuclei DNA binding protein (Nuclear) ❖ Three major classes of surface receptors for signaling: Ion-channel linked receptors, G-protein coupled receptors (GPCR), Enzyme-linked receptors 1. Ion-channel linked receptors A ligand binds to the receptor ➔ opening or closing a channel 2. G-protein coupled receptors (GPCR) They are transmembrane proteins that have 7 transmembrane helical domains GPCR ligands include Neurotransmitters (NT), Hormones (H) or even light Targets of GPCRs are plasma membrane bound enzymes or ion channels The first discovered G-protein coupled receptor was Rhodopsin (It is discovered by X-ray crystallography) Rhodopsin exists in retina, used for low light vision ➔ It has no ligand it is activated by light Approximately 800 different GPCRs are encoded in the human genome but they all have the same mechanism of actions GPCR are linked to G proteins is heterotrimeric = made from 3 different subunits (α, β, γ) α and γ are lipid anchored (covalent bonds) to the cytosolic surface of the membrane  ❖ Mechanism of Activation of GPCRs: a) Binding of ligand to extracellular domain of GPRs induces conformational change that allows cytosolic domain of the receptor to bind to inactive G protein (by α subunit) ➔ Activating G-proteins b)  subunit can now bind GTP instead of GDP, causing dissociation into activated  &  subunits. Each of these can go on to activate target proteins ✓ When  subunit binds to GTP it become active and free (dissociate from  subunits) ➔ so Activated  subunit goes to its target, also  subunits can go to their target (For example G inhibits one of several isoforms of Adenylate Cyclase, contributing to rapid signal turn off) ✓  subunits complex is inhibitory for  subunit c) Immediately after G activates the effector, it must become inactivated by the hydrolysis of GTP that is bound to it and thus it is replaced by GDP and it rebinds with the G , complex and become inactive complex G-proteins have many types according the activity of their  subunit: Gs ➔ Activate Adenylyl cyclase ➔ increase cAMP (linked to -adrenergic (epinephrine) receptor & the receptors of Glucagon, serotonin and vasopressin) GI ➔ Inhibits Adenylyl cyclase ➔ Decrease cAMP ( 2 -adrenergic receptor) ✓ Its G subunits activate K+ channels ➔ change membrane potential (Ach Muscarinic receptor) Gq ➔ Activates Phospholipase C (PLC) ➔ produce IP3 & DAG (1-adrenergic receptors) ✓ When activated ➔ vasoconstriction occurs in the smooth muscles in the blood vessels Go ➔ Activate PLC ➔ produce IP3 & DAG (Acetylcholine [Ach] receptors in endothelial cells) Protein kinase ➔ It phosphorylated the protein using ATP Protein phosphatase ➔ removes the phosphate groups from protein (dephosphorylation by hydrolysis reaction) Protein kinases and phosphatases are themselves regulated (turned on and off) by complex signal cascades, ❖ Turn off of the signal: The signal should be turned off to avoid over regulation (so that the cell can be receptive for another stimulus after the first signal causes the required action), It could be happen by different ways : 1. GTPase hydrolyzes GTP to GDP + Pi ➔ G rebinds to the inhibitory  complex 2. Phosphodiesterases catalyze hydrolysis of cAMP to AMP (cAMP + H2O ➔ AMP) The phosphodiesterase that cleaves cAMP is activated by phosphorylation catalyzed by Protein Kinase A Thus cAMP stimulates its own degradation, leading to rapid turnoff of a cAMP signal (negative feedback) 3. Receptor desensitization (varies with the hormone) The activated receptor is phosphorylated via a G-protein Receptor Kinase ➔ then it may bind to a protein -arrestin ➔ -Arrestin(like tag on the receptor) promotes removal of the receptor from the membrane by clathrin mediated endocytosis Another way -Arrestin may also bind a cytosolic Phosphodiesterase, bringing this enzyme close to where cAMP is being produced, contributing to signal turnoff 4. Protein Phosphatase catalyzes removal (by hydrolysis) of phosphates ➔ so inhibiting the protein Small GTP-binding proteins include: Initiation & elongation factors, Ras, Rab, ARF, Ran, Rho GTP-binding proteins differ in conformation (active & inactive) depending on whether GDP or GTP is present at their nucleotide binding site. Generally, GTP binding induces the active state Most GTP-binding proteins depend on helper proteins: GAPs & GEF  ❖ GAPs: ❖ GEF : GTPase Activating Proteins Guanine Nucleotide Exchange Factors Promote GTP hydrolysis Promote GDP/GTP exchange G has innate capability for GTP hydrolysis ➔ because it An activated receptor(GPCR) normally serves has the essential arginine residue normally provided by as GEF for a heterotrimeric G-protein a GAP for small GTP-binding proteins 3. Enzyme linked receptors: It is classified into: 1) Tyrosine Kinase-Linked receptors (TKRs) ➔ These receptors have enzyme called Tyrosine kinase in intracellular part of the receptor (it is a part of the receptor [Intrinsic enzyme]) 2) Tyrosine Kinase non-covalently associated with receptor (NRTKs) ➔ TK is associated to these receptors, it’s not part of the receptors. 3) Receptors associated with other types of enzymes ❖ TKRs Cell surface receptors that are directly linked to intracellular enzymes (kinases) Includes receptors for most growth factors (NGF, EGF. PDGF), insulin (it is the most famous) and Src Structure: N terminal extracellular ligand-binding domain, single TM domain, cytosolic C-terminal domain with tyrosine kinase activity Can be single polypeptide or dimer (can consist of one or more units), such as: Insulin receptor is a dimer Mechanism of activation of TKRs: When Ligand bind to receptor, it induces dimerization (cross linking) of 2 units Dimerization leads to autophosphorylation of the enzyme in the receptor (cross phosphorylation) ➔ It means that there will be phosphate groups in the intracellular domain (tyrosine becomes phosphorelated) Phosphorylation increases kinase activity ➔ Then phosphate groups can bind to other molecules, for example: adaptor protein links Ras GEF to the receptor ➔ then RAS GEF adds a phosphate group to GDP on the Ras protein Explanation of insulin receptor mechanism: Insulin receptor consists of 2 units that dimerize when they bind with insulin Insulin binds to ligand-binding site on the plasma membrane activating enzymatic site in the cytoplasm (intracellular domain) ➔ Autophosphorylation occurs, increasing tyrosine kinase activity ➔ activates signaling molecules called IRS (Insulin receptor substrates or insulin downstream targets), leading to: ✓ Stimulate glycogen, fat and protein synthesis (anabolic reactions) ✓ Stimulate insertion of GLUT-4 proteins, to facilitate entrance of glucose into the cell (Glucose uptake) ✓ Growth & gene expresion ❖ NRTKs Tyrosine Kinase non-covalently associated with receptor (Such as cytokine receptors, T & B cell receptors) Structure: N-terminus (extracellular ligand-binding domain), transmembrane -helix and C- terminus (cytosolic domain) ➔ Cytosolic domain has no catalytic (kinase) activity Activation is similar to that of RTKs: ligand binding causes cross phosphorylation of associated tyrosine kinases that phosphorylate the receptor, providing phosphotyrosine binding sites for recruitment of proteins with SH2 domains Two kinds of kinases associate with NRTKs: Src family protein kinases - important for B and T cell signaling (‫)مش مطلوب‬ Janus kinases (JAK) required for signaling from cytokine receptors (Leptin)  ❖ Receptors can be linked to or associated with other enzymes, beside TKs Protein-tyrosine phosphatases: Remove phosphates, instead of adding phosphates, thereby terminate signals initiated by protein- tyrosine kinases Serine/ threonine kinases ➔ TGF-β Guanylyl cyclases: Receptor guanylyl cyclase has guanylyl cyclase as a part of it ✓ it is involved in ANP & NO signaling, by: Membrane receptor ➔ ANP Soluble receptor ➔ NO, CO ❖ Leptin receptor Lipten bind its receptor ➔ induces phosphorylation of JAK 2 ➔ that induces phosphorylation of Stat3 molecules ➔ Stat3 dimerise and enter the nucleus to induce transcriptions of certain targets STAT= Signal Transducer and Activator of Transcription JAK 2 phosphorylation also activates several other enzyme systems that mediate some of the more rapid effects of leptin Leptin receptor exists as a homodimer (two identical parts) Leptin is an important hormone of satiaty, and lipid-tissue metabolism ❖ Second Messengers Second messengers are required for intracellular signaling, especially for hormones that cannot pass the plasma membrane (polar, water-soluble hormones) Examples on 2nd messenger ➔ cAMP, cGMP, IP3 & DAG, Ca+2, PIP3 ❖ cAMP: most common Synthesis: Adenylate cyclase (large multipass transmembrane protein) converts ATP into cAMP Degradation: cAMP phosphodiesterase Action of cAMP: Its target is ➔ cAMP-dependent protein kinase = protein kinase A (PKA) Binding of cAMP to PKA activates it ➔ it phosphorylates other target proteins & regulates their activities PKA is a tetramer of catalytic and regulatory subunits ▪ cAMP binds to the regulatory subunits leading to dissociation of them and release of catalytic subunits which then phosphorylate target proteins in cytoplasm ▪ PKA has 2 Functions ➔ phosphorylation of target proteins & changing gene expression by: ✓ PKA enters the nucleus directly (through the nuclear pores) ➔ here it is considered as a third messenger ✓ PKA phosphorylates CREB (CRE binding protein) ✓ CREB binds to the (CRE) and activates it ➔ activation of transcription of those genes CRE (Cyclic-AMP Response Element) is a regulatory DNA sequence associated with specific genes Hormones use cAMP: FSH, LH, ACTH, TSH, CRH, hCG, PTH, Calcitonin, Glucagon, GHRH (via IP3) Pathogens can alter cAMP production (abnormalities in cAMP production) Cholera toxin active subunit catalyzes transfer of ADP ribose from intracellular NAD to the α subunit of Gs, causing it to be continuously active, stimulating adenylyl cyclase indefinitely ➔ This causes ion channels in GI tract that export chloride to produce a net efflux (secretion) of chloride ions Cl- and water, leading to severe diarrhea, a characteristic of cholera Various metabolic responses depend on the tissue itself; different responses might include the same receptor and 2nd messenger, this is mainly due to the different cell types in different tissues  ❖ cGMP: cyclic guanine monophosphate Produced from GTP by guanylyl cyclase Target: activates cGMP-dependent kinases (protein kinase G) or other targets Examples on signaling pathway that produces cGMP as a 2nd messenger: a) G-protein Coupled rhodopsin photoreceptor in rod cells of retina. b) Nitric oxide signaling & ANP signaling ❖ IP3 and DAG: Gqα activates phospholipase-C that converts (hydrolyzed) PIP2 into diacylglycerol (DAG) & inositol 1,4,5- triphosphate (IP3) PIP2 is Phosphatidylinositol 4,5-bisphosphate - A minor phospholipid in inner leaflet of the plasma membrane bilayer - It is produced by phosphorylation of phosphatidyl- Inositol & it is involved in signaling After PIP2 is hydrolyzed ➔ DAG still connected to PM, but IP3 become free in the cytosol ➔ and both act as 2nd messenger PIP2 hydrolysis is activated by both GPCRs and TKRs via different forms of PLC: Phospholipase-C beta (PLC-β) is stimulated by Gq proteins Phospholipase-C gamma (PLC-γ) has SH2 domains that allow binding to activated tyrosine kinase linked receptors ✓ IP3: It will bind to a receptor on the endoplasmic reticulum (ER) membrane which results in opening calcium ion channels on ER membrane and release of calcium ions from their stores into the cytosol increasing intracellular calcium levels ➔ activating a protein kinase C PKC along with DAG SERCA channels ➔ Turns off the calcium signal ➔ pumps the calcium ions back to their stores in the ER to bring calcium levels back to their normal levels Hormones use IP3: GnRH, Gastrin, Oxytocin, TRH, ADH (V1), Histamine (H1), Angiotensin II ✓ DAG: Stimulates the Ca+2-dependent protein kinase C signaling pathway, which activates other targets (including the MAP kinase cascade) ❖ Ca+2: Ca+2 concentration is kept low (10-7 M) and rises locally due to transient signaling via IP3 Ca+2 acts as a second messenger on its target proteins ➔ calmodulin The effects of intracellular Ca+2 are mediated by the Ca+2 binding protein calmodulin ➔ conformation of calmodulin changes forming Ca+2/ calmodulin complex Ca+2 /calmodulin complex binds to other target proteins, regulate their activity, and fully activate them, such as: ✓ Protein kinases (Ca+2 calmodulin dependent kinases; CaM-kinases) ✓ Adenylyl cyclases ✓ Phosphodiesterases & Protein phosphatase The same hormone can active two different types of receptors which results in production of two different types of second messengers in the same cell Such as Epinephrine & its effect on a liver cell… Epinephrine binding to beta-adrenergic receptors (GPCR) ➔ activating Gs ➔ increase cAMP ➔ activation of PKA ➔ increase glycogen metabolism and production of glucose in the liver Epinephrine binding to α1 adrenergic receptor ➔ activating Gαq ➔ activating PLC ➔ produce IP3 & DAG ➔ increasing calcium levels ➔ activating protein kinase ➔ increasing the glycogen metabolism  ❖ Guanylate cyclase (GC) receptors ANP (Atrial Natriuretic Peptide) signaling: It is a hormone secrete by the atrium, and an antihypertensive agent Its main function is to lower blood pressure NO signaling NO synthesis: In blood vessels there are endothelial cells and smooth muscle cells In endothelial cells there are acetylcholine G-protein coupled receptors that binds with acetyl choline ➔ associated with Gαo subunit ➔ The binding induces activation of PLC PLC ➔ IP3 ➔ Ca+2 /calmodulin complex ➔ activates an enzyme called nitric oxide synthase that synthesizes NO from arginine amino acid NO is a gas that can freely diffuse across the PM and goes to adjacent smooth muscle cells, it will bind to a receptor called NO receptor, which is a soluble receptor This receptor contains guanylyl cyclase activity, which converts GTP into cGMP cGMP (2nd messenger) ➔ bind to protein kinase G ➔ relaxation of the muscle cell which results in vasodilation of vessels NO is an important antiplatelet and vasodilator ❖ PIP3: ▪ 2nd It is a messenger ▪ PIP2 is phosphorylated by PI 3-kinase producing PIP3 ▪ It contributes in the survival of the cell by inhibition of apoptosis PDK and PKB Intracellular receptors: (Steroid receptors & Thyroid receptors) Receptors for lipophilic hormones are called nuclear hormone receptor ❖ Steroid receptors Steroid receptors are located in cytoplasm and in the nucleus Function within cell to activate genetic transcription ✓ Messenger RNA directs synthesis of specific enzyme proteins that change metabolism The nuclear receptor has 2 main regions ➔ ligand (hormone)-binding protein & DNA-binding protein Receptor must be activated by binding to hormone before binding to specific region of DNA called HRE ✓ HRE (hormone responsive element) it is a region of DNA in which the DNA-binding protein binds, and it is located adjacent to gene that will be transcribed Mechanism of steroid hormones: Cytoplasmic receptor binds to steroid hormone ➔ then Translocated to nucleus ➔ DNA-binding domain binds to specific HRE of the DNA Dimerization of receptors occurs (2 receptors units becoming together with 2 half-sites) Stimulates transcription of particular genes The mechanism of thyroid hormones: ▪ T4 passes into cytoplasm and is converted to T3 by iodinase ▪ Receptor proteins located in nucleus (TR receptor dimerises with RXR receptor to form a heterodimer) ✓ T3 binds to ligand- binding domain ➔ on the TR receptor ✓ Other (ligand) half-site is vitamin A derivative (9-cis- retinoic) acid ➔ on the Retinoid X receptor ▪ DNA-binding domain can then bind to the half-site of the HRE ➔ Stimulate gene transcription ▪ This Mechanism acts in: Growth & Metabolism, CNS, Cardiovascular and many other systems  What determines the activity of a hormone? 1) the concentration of the hormone that is available for binding (conc. of free hormone level) ➔ it is determined by secretion of the endocrine system. 2) the conc. Of carrier-bound hormone 3) the conc. Of hormones bound to the receptor 4) the level of hormone degradation (clearance) in the body Clearance is the rate of disappearance from plasma / conc. In plasma Thyroid hormones (Thyroxine & Triiodothyronine) ➔ high protein binding in the plasma ➔ protected from clearance (very low) ➔ long half life Protein hormones (Thyrotropin, Insulin & Antidiuretic hormone) ➔ low protein binding in the plasma ➔ not protected from clearance (very high) ➔ short half life ❖ FSH and LH secretion FSH and LH are female sex hormones that are secreted by anterior pituitary gland 1) hypothalamus secretes GnRH (gonadotropin releasing hormone) reaching the anterior pituitary gland where its receptors are located (GnRH- receptor) 2) GnRH-receptors are GPCR ➔ with Gqα subunit ➔ activate the phospholipase C to produce DAG and IP3 ➔ increases the Ca++ in the cytosol ➔ activate protein kinase C to perform specific functions. 3) also the Ca++ activates the exocytosis of the vesicles containing FSH &LH to go to the future ovaries ❖ Third messengers: Third messengers are the molecules which transmit message from outside to inside of nucleus or from inside to outside of nucleus Also called DNA binding protein (carrying a signal enter the nucleus)  ‫تفاصيل الدورة المكثفة )المراجعة(‪:‬‬ ‫شرح المادة كاملة في أقل من ‪ 7‬ساعات‬ ‫ ‬ ‫الشرح والمخلص شاملين كل شي باذن هللا‬ ‫ ‬ ‫الملخصات موجودة في مجموع التيليجرام باألسفل‬ ‫ ‬ ‫سعر المراجعة‪ :‬خمسة دنانير فقط‬ ‫ ‬ ‫كيفية التسجيل‪:‬‬ ‫‪ )1‬الدفع اما عن طريق زين كاش للرقم ‪ 0792870752‬أو بيجيك مندوب من الموقع للدفع‬ ‫‪ )2‬عمل حساب على موقع ‪Medlearn-jo.com‬‬ ‫‪ )3‬تعئبة الفوم التالي‬ ‫‪https://forms.gle/n92jYxwBB8XwnpAd9‬‬ ‫عشان نضيف لك المراجعة ان شاء هللا🔥🔥‬ ‫‪Medicine with Dr.Ahmad‬‬ ‫‪medicine_with_dr.ahmad‬‬ ‫‪https://t.me/+5phjc9oVBchlNTJk‬‬ ‫‪https://chat.whatsapp.com/FqYqxIz4X38J1Z7vW3gkPE‬‬