Nervous System Notes PDF

Lecture 6: Nervous system I There are about 100 billion neurons in the human brain. Nerve Tissue function & organization: - A neuron contains an axon which is an electrical conductor for bioelectricity as it carries the electrical signal from the axon hillock to the presynaptic terminals a...

Lecture 6: Nervous system I There are about 100 billion neurons in the human brain. Nerve Tissue function & organization: - A neuron contains an axon which is an electrical conductor for bioelectricity as it carries the electrical signal from the axon hillock to the presynaptic terminals at the bottom of a neuron 1. Neuron cells → carry electrical signals through the dendrites (long branched structures that collect the incoming signals)→ electrical signals add up in the axon hillock transmitting a signal down the axon to the synapsis (a gap between neurons that sends information) - Signals jump from node of ranvier (gaps in the myelin sheath where ions are exchanged across the axon membrane; contains high concentrations of voltage-gated sodium ion channels) to the next (this process is called saltatory conduction & is contributes to action potential) - The Axon Hillock is where all electrical signals are summed & determines the final potential to compare to threshold potential & decides if an action potential will be fired 2. Glial cells (oligodendrocytes specifically insulate the central nervous system) & schwann cells (a specific type of glial cell only found in the peripheral nervous system)→ support electrical insulation such as the myelin sheath 3. The Cell Body of a neuron consists of the nucleus & other organelles Potential: Bioelectricity in the neurons exists due to a voltage of about -70 millivolts per neuron → to have a voltage there must be a generator that builds up charge: - The generator is an ATP consuming pump located in the plasma membrane of cells/neurons - This form of energy creates an ion gradient as a result of the differences in ion concentrations inside and outside the cell a. Sodium potassium pump is the energizer of our neurons/all of our cells 1. Takes chemical energy in the form of ATP 2. ATP is hydrolyzed (reaction where water breaks a chemical bond) 7 becomes ADP while releasing phosphate to build up the chemical gradient where energy is released 3. Once the energy is released → the pump uses it to pump 3 sodium ions outside of the cell & pumps 2 potassium inside of the cell 4. The inside of the cell is negatively charged & the outside of the cell is positively charged/ zero/ at ground Slicing an axon/ movement of molecules example: - 150 mM Na+ is outside of the axon → in the end, 15 mM Na+ is inside the cytoplasm of the axon - 150 mM K+ is inside the axon → in the end, 15 mM K+ is outside of the axon in the interstitial fluid (fluid that surrounds the cells) - Chloride is important for relaxation → 120 mM Cl- outside the cell → in the end, 10 mM Cl- is inside the cell Resting potential (or resting voltage): - Potential = voltage - Why resting potential -70 mv (or -40 to -70)? What does it mean? a. It means that the voltage inside the axon is -70 at rest compared to the outside (potential energies are always relative to something else, therefore the outside is zero/at ground but the inside is more negative) - To get a resting voltage of -70, the membrane surrounding the axon is impermeable (doesn't allow fluid to pass through) to the sodium gradient (if it were permeable then the resting voltage would increase because sodium would make the inside more positive) - The sodium gradient is held in place when the neuron is at rest AND there is still permeability to potassium due to potassium channels that are passive to potassium (allows potassium to leak out) - Positive charges are being released from the inside of the cell because potassium goes down its gradient (out of the cell) → and the inside gets more negative - At rest there are more Na+ (sodium) and Cl- (chlorine) ions outside the cell while more K+ (potassium) ions are concentrated inside the cell Bioelectricity equation (to calculate which voltage is negative enough in the cell to stop the gradient from leaking out)→ Equilibrium potential a. As potassium flows out the inside becomes negative (this is the chemical chemical force) b. Electrical force is when opposite charges attract one another c. Therefore, potassium stops flowing out when the [chemical force = electrical force] thus the equation… Equation: Room temperature → 58 mV (the second line on the pic is the equation) - Z is the charge of the ion for example → Na+ = +1 or Cl- = -1 or Ca2+ = +2 - - The neuron voltage is still -70 because there's also a sodium channel that allows some of the sodium to leak in (very little) Action potential: - Goes from resting potential → threshold potential → action potential. - It only occurs if the depolarization crosses the threshold potential (depolarization = the cell becomes less negative/more positive) - Starts from the axon hillock & travels down the axon to the terminals 1. Resting potential is when potassium flows out & holds the negative voltage (the sodium is held in place) - Hyperpolarization → more negative inside than at rest (k+ is leaving the cell) - Is maintained at -70mV by the Na+ & K+ activity 2. Threshold potential is when the membrane suddenly because permeable to sodium ions (sodium channels open to get a positive voltage) - First, the axon hillock senses that cumulative signals are over the threshold potential - Sodium channels depolarize the neuron enough to cause the resting potential of -70 voltage to positive voltage on the inside of the membrane of the neuron of up to +50 mV (voltage) - Depolarization → more positive inside (Na+ entering the cell) 3. Action potential is reached as a result of the sodium channels opening & more sodium is rushing in - Only happens when the threshold potential is passed - depolarization first → to -50 mV → channels open - Membrane potential becomes more positive → more sodium channels open - Some k+ are still able to go in but very slowly 4. Action potential goes down, even below the resting potential (repolarizes) - Sodium channels inactivation (the way a door closes after its been opened which is why the action potential does not stay positive) - Rapid repolarization is also happening & occurs by voltage dependent potassium channels 1. Activated by depolarization potassium channels open (slower than sodium channel) 2. Potassium flows out = Repolarization 5. Ultimately becomes more negative & below the resting potential because a lot of potassium is rushing out 6. Then it goes back up to match the resting potential because it's more negative inside and it shuts down the channels. TTX (a neurotoxin) → blocks sodium channels → which stops action potentials & stops breathing & you couldn’t survive - Puffer/Fugu fish synthesize TTX Lecture 8: Nervous system II Degrade = inactivate Propagation (spread) of Action Potential (how it moves down the axon): The axon hillock moves down to the terminals in a unidirectional movement by jumping from one node to the next node (which is called saltatory conduction)  - First action potential: sodium rushes in through depolarization (the cell becomes positive on the inside) and the leftover sodium ions + the charge inside the cell affect the membrane next to it so that it also depolarizes (opens sodium channels) and so on - Also occurring after the sodium channels close Potassium flows out of the cell (the cell returns back to negative) through the delayed opening of the voltage dependent potassium channels - The action potentials deplete over time because the gradient of sodium & potassium depletes - There is no back propagation because… 1. voltage -dependent potassium channels (when sodium rushes in, potassium rushes out and it brings the voltage back down to -80 millivolts & the undershoot closes the sodium channels) 2. Action potentials start in the cell body (takes into account the direction) 3. Refractory period (recovery time for the voltage dependent sodium channels → like dominos, once down you have to wait until they are all up again) - The refractory time is fast - Action potential velocity down a motor neuron → 120 m/sec - Saltatory conduction → Action Potentials jump from one node of Ranvier to the next (this makes it faster) a. In myelinated neurons, the myelin sheath acts as an insulator, preventing current leakage and allowing for faster signal transmission (increases speed) by "jumping" between nodes of Ranvier where the membrane is exposed - It is produced by schwann cells in the PNS and by oligodendrocytes in the CNS that increase the speed of the electrical impulses b. Unmyelinated sections are also present between the nodes of Ranvier that help in regeneration of electrical signals as they are full of voltage gated sodium channels which do not let action potentials degrade - Multiple sclerosis (MS) → an autoimmune disease (when the immune system mistakenly attacks itself) that damages the protective coating (myelin sheath) around nerve cells in the brain and spinal cord a. The immune system starts degrading the myelin sheets because it doesn't recognize them as a “self” tissue b. Drugs have been progressing to not suppress the immune system but instead to reduce the inflammation caused by the degradation of the myelin sheets Other types of electrical potentials that makeup the nervous system: a. Postsynaptic potentials b. Generator potentials Synaptic Transmission → In neurons signals can be processed and responded to quickly a. Electrical synapse (John Eccle contributed) → direct contact like a cardiac muscle (an electrical connection from one cell to another including a pacemaker that causes contractions in a wave because of the gap junctions in between the muscle cells) b. Chemical synapse (Bernard Katz contributed) → a chemical that diffuses to the next cell and binds to a receptor and then the next cell communicates on 1. The action potential reach the axon terminals and arrive at the end of the presynaptic knob (the synaptic knob) and causes the voltage-dependent calcium ion channel to open (allows calcium to go into the cytoplasm) 2. Calcium is the second messenger that causes vesicles which contain neurotransmitters inside the presynaptic membrane to bind/fuse with the postsynaptic membrane - The vesicles’s (thousands of them) content is dumped when calcium goes up 3. The space between two neurons is called the synaptic cleft & a neurotransmitter is released only at the postsynaptic membrane if the receptor is for it (neurotransmitters bind to the receptors ion channels on the postsynaptic membrane) 4. Most of the neurotransmitter receptors are ion channels and the sodium influx depolarizes postsynaptic cell & if there are enough of the signals it will cause an action potential to fire 5. Afterwards, the neurotransmitter has to be removed by enzymes in the synaptic cleft that degrade the neurotransmitters (this is important in muscle contraction) a. Another way to degrade a neurotransmitter is by uptake them again (transport them back into the presynaptic neuron and package them again into vesicles so that when a neuron is fired, there are now vesicles with neurotransmitters) - Well known drugs can affect the reuptake of neurotransmitters such as antidepressants (act by inhibiting the repackaging of the neurotransmitter so that it stays in the synapse longer) Neurotransmitters (present in the presynaptic cells) → chemical compound a. Anatomically → the NT is packaged in synaptic vesicles in the presynaptic cell & it secretes when the action potential arrives b. Physiological → NT only has an effect on the postsynaptic cell when injected to the synaptic cleft c. Biochemical → NT is rapidly removed by enzymatic breakdown and reuptake in the cell - The neurotransmitter receptor on the postsynaptic cell opens a sodium permeable channel (4) that depolarizes which contributes to the excitatory postsynaptic potential a. Excitatory neurotransmitters: depolarizes the membrane potential - glutamate (an amino acid) at a very low concentration in the brain can fire action potentials at a synapse WHILE in the bloodstream there are higher concentrations of glutamate - Acetylcholine in the neuromuscular synapse (motor neurons innervating a muscle releasing a neurotransmitter telling the muscle cell to depolarize and contract) - EPSP form by positive sodium or calcium 2+ influx (entering) b. Inhibitory neurotransmitters: hyperpolarize membrane potential - Glycine → major inhibitor in the brain - gamma-amino -Butyric-Acid (GABA) → major inhibitor in the brain - Sedatives stimulate the IPSP (inhibit postsynaptic potentials) to be stronger which makes it harder to fire an action potential (can also become addictive) - IPSP can form by negative chloride influx (entering) or positive potassium efflux (leaving) - Illegal drugs or certain medications cause inhibition of dopamine reuptake in neuron synapses such as cocaine which leads to a dopamine rush effect or amphetamines Lecture 9: Sensory System Ion channels (make up action potentials & play a role in synaptic transmission): a. Receptor ion channels in the postsynaptic membrane → Na+, Ca2+, Cl-, K+ - Excitatory: Sodium & calcium permeable channels cause a more positive voltage inside - Inhibitory: voltage inside gets more negative b. Voltage-dependent channels → Na+, K+, Ca2+ - In the actual action potential (depolarization through sodium and repolarization through potassium) - Calcium channels in the presynaptic knob (Explained in last lecture) c. Few K+ channels open (resting potential) Sensory systems: - Signaling input: a. Mechano receptors (touch receptors that respond to mechanical stimuli) b. Chemo receptors (ex. Olfactory & taste receptors) c. Electromagnetic receptors (ex. light/visual receptors) d. Thermo receptors e. Pain receptors - Capsaicin is responsible for the burning sensation that comes from spicy food and directly stimulates the pain-stimulating neurons - Low dose of capsaicin open and send weak signals & more capsaicin open more channels and results in more depolarization and steepness Generator potentials in the sensory neurons: - Neurons in the brain process information through frequencies - The generator potential gives a sensory input - How does a neuron know if a temperature is really hot so that it sends a signal to the brain? a. When touching a hot surface, the action potential gets fired earlier there are more action potentials being encoded meaning a higher frequency (creating a steeper slope on a graph) - When temperature increases the generator potential is more steep b. Higher frequency = stronger stimulus & lower frequency = weaker stimulus - More action potentials/time = the frequency increases Mammalian eye: - An example of amplification in the sensory system a. Structure b. Light receptors in the retina: - Rods → very light sensitive black/white vision (125x10^6 rods in human eye) & allow us to see at night/in darkness - Cones → detect color such as blue, green, red (6x10^6 cones in human eye) - We can see colors when the light is bright enough - The receptors (rods/cones) use the same principle to detect light → they both require vitamin A to produce retinol that is embedded in the receptors so that a quantum can change the receptor c. Molecular mechanism: - In plants the thylakoid membrane has a high density of photosynthetic reaction centers that capture light - Membrane protein with built in prosthetic group → the prosthetic group is the opsin & retinal → which makes up the Rhodopsin d. Visual sequence: how is light amplified? 1. Rhodopsin absorbs photons through hitting the prosthetic group (the retinal) - A light hits the photon receptor and this activates the protein with built in prosthetic group (also changes its shape) → then another protein (Transducin) attached to the protein gets bumped off the receptor and activates an enzyme called phosphodiesterase (PDE) → PDE then degrades a molecule called cyclic GMP and removes it from the ion channel 2. Then activates intracellular cascade of events that causes amplification - Dark/depolarized: Na+ sodium channels open & there are inactive rhodopsin - Light/hyperpolarized: Na+ channels closed & active rhodopsin - Photons are at high density overall so that the the photoreceptor is not missed 3. Then that causes a change in membrane potential 4. Change in neurotransmitter output at synapse - Dark = resting potential of -40 (not firing action potentials) - When the light is on, the cyclic GMP is removed and the sodium channel closes getting closer to the resting potential - Light causes negative hyperpolarization (opposite for flies & salamanders) Additional cell types in the retina: they detect light, process information, and transmit it to the brain - Photoreceptors that are rods (black or white) or cones (color) - Ganglion cells → go from the photoreceptor cells to ganglion cells that go inside the brain to the optic nerves - Bipolar cells → connect the photoreceptor cells to the ganglion - Horizontal cells → if you stimulate one photoreceptor the horizontal cells will act on the neighboring receptors (they do lateral inhibition/ connect) - Amacrine cells → enhance the stimulus (increase the brightness, amplitude, or signal) Optic nerve: - Lens inverts the image (right eye seems left visual field & left eye sees the right visual field) - There is an area in the brain that represents an electrical stimulus screen and processes information Lecture 10: Sensory System II Hearing: - Action potentials can start just by the movement of hair cells that initiate the process - The outer ear (funnel shaped) lets in acoustical waves (vibrations) into the ear a. At the end of the outer ear there is a tympanic membrane (also known as eardrum) where pressure waves move the membrane and this causes  the malleus, incus, and stapes (all bones) to move in the middle ear b. Sound waves are pressure waves transmitted by the air to mechanical movements to the bones then to waves inside a fluid in the inner ear (the cochlea) - Middle ear (mechanical) & can be damaged easily - Inner ear: a. Cochlea is in the inner ear → movements of the stapes (from the middle ear) onto the oval window causes pressure waves in the liquid inside the cochlea that move through the vestibular canal to the tympanic canal - In order for the waves not to cause interference (considering that they can bounce back in liquid) energy is released at the end of the tympanic canal called the round window - The wavelength of the waves in the liquid depends on the frequency → Higher pitches will have higher frequency and shorter wavelengths & lower pitches will have lower frequency and longer wavelengths - The sound frequencies are perceived by the auditory nerve (the fibers of the sensory neurons) that innervate through hair cells inside the cochlea a. On the basilar membrane are hair cells that create resonance depending on the frequencies & hit the tectorial membrane which open ion channels that depolarize hair cells as a generator potential that eventually sets off action potentials in the auditory nerve that goes to our brain → then hearing b. In order to hear, sound needs to be broken into different frequencies on different parts of the basilar membrane and ion channels open up through the mechanical stress - If the hair cells were equally stiff then we would not be able to determine which frequencies are present - Hearing is a pressure wave a. Sound waves: pressure waves are transmitted by particles in the air or in water - In a Vacuum there is no sound transmittance - The velocity of sound in air is 300 m/sec - The velocity of light is 3x10^8 m/sec - Velocity = (wavelength)(frequency) Muscle Control: - Muscle structure: a. Muscle → Bundle of muscle fibers → within a muscle fiber there are multiple muscle cells (a single cell/ single part of a muscle can only produce a very low energy) - Muscle cells have multiple nuclei because they develop really long - Myofibrils → a muscle cell can have 10-20 of them & they are the functional unit of a muscle cell that allows contraction (they consist of thin (2 strands of actin + 2 strands of regulatory proteins) and thick filaments (myosin proteins)) → a sarcomere refers to a unit that includes the thin and thick filaments and an H zone where there are grey filaments - Sliding filament model → the thin filaments slide inwards & the thick filaments pull the z lines closer to the center of the sarcomere → this leads to a type of contraction where the length gets shorter but when the muscle is relaxed its longer - The energy for the sliding filament model comes from the power stroke sequence of events of muscle contraction: - Ach binding → Na+ influx → Ca2+ release, actin-myosin binding, power stroke, ATP binding 1. A myosin head binds to actin (consists of 2 braided actin filaments with balls attached where the myosin heads attach/bind themselves) - If there were no ATP the muscles would lock up since the myosin starts binding to the actin → in rigor mortis the body because stiff because the myosin heads are locked in place & no longer coming off 2. When ATP is added, the myosin head that is bound to the actin filament gets released and it opens up - ATP is then hydrolyzed to ADP + inorganic phosphorus (stable) 3. The myosin head is detached from the actin filament but now the ADP + inorganic phosphorus causes the myosin head to bend to the right and attach to new binding sites on the actin filament 4. The ADP then gets kicked off creating a power stroke where the myosin head bends back to the left pulling the actin to the left as well  - One power stroke creates a force of about 1-2 piconewtons 5. There are also two other braided filaments that regulate muscle contraction - In a relaxed sarcomere there is tropomyosin that cover up the binding sites in a relaxed muscle (the myosin head can't grab on even though there could be ATP & power strokes) - In a contracted muscle → troponin complex (proteins) have calcium binding sites that causes muscles to contract a. Calcium ions rise in the cytoplasm as calcium atoms that bind to the troponin complex which causes the binding of calcium causing the braid of tropomyosin to rotate which allows the myosin heads to bind & initiate muscle contraction - If there are no calcium atoms then there is no muscle contraction b. The resting calcium concentration is about 0.15 micromolars but when an action potential comes, calcium flows into the presynaptic then the concentration increases to 1-2 micromolars (this is the range that allows the binding to the troponin because it has evolved to have a calcium binding site with that attraction/affinity) c. Depolarization of the muscle/ Excitation→ when an impulse arrives at the neuromuscular junction, causing the release of acetylcholine which binds to receptors on the muscle cell membrane, leading to the opening of sodium channels and an influx of positive ions, thus changing the electrical potential across the membrane, making it less negative and initiating an action potential that spreads throughout the muscle fiber, triggering contraction - This causes contraction because of the voltage dependent sodium channels - Action potentials propagate away from the neuromuscular junction in all directions along the membrane (because muscle cells are really long) to get electrical propagation - Skeletal Muscles can contract strongly & rapidly, therefore the myofibrils also have to be affected and this occurs through the tunnels of plasma membrane that allows the action potential to reach it (depolarize and reach the myofibrils) HOWEVER in smoother muscles, contraction is slower - Sarcoplasmic reticulum → allows the muscle to contract rapidly - There are also voltage calcium channels in the t tubules that are opened when the sodium channels open and so the calcium flows in from the interstitial fluid and have a structure that bumps into the sarcoplasmic reticulum → it causes them to have concentrated calcium and to release (by calcium induced calcium release meaning that calcium encourages the release of calcium) into the cytoplasm that binds to the troponin then contraction occurs THEN after calcium is removed quickly through calcium pumps - If there were no skeletal muscle then there wouldn't be t tubules but there would still be sodium channels to propagate action potentials - T tubules → allow for deepness of the muscle Neuromuscular diseases: - Amyotrophic lateral sclerosis (ALS) → motor neuron degeneration where there can be a lot of different mutations - Myasthenia Gravis → Acetylcholine receptors not concentrated in synapses (there are less) causing a weak muscle contraction - Lambert Eaton syndrome → the presynaptic calcium channels are weaker so there is not as much neurotransmitter release - Dysgenic muscle in mice → unable to contract due to the failure of excitatory contraction (in the t tubules/ release of calcium) - Duchenne muscular dystrophy → degenerate development to non-muscle cells meaning that instead of turning on a muscle cell, you turn on the development of non-muscle cells for example fat cells - Tetanus → caused by a bacterial infection that affects neurons in the brain - Botox → the most neurotoxin that there is where it inhibits the release of the acetylcholine Lecture 15: Hormones Endocrine system → hormones are secreted into the bloodstream a. Hormone secreting glands/ Endocrine glands: they secrete via exocytosis/ vesicle secretion of hormones into the circulatory system meaning that the secretion happens within the body & stays in the bloodstream of the hormone b. Exocrine glands: secretion via ducts such as sweat, mucus, digestive enzymes, & non-hormones - Includes digestive juices/enzymes (in pancreas/digestive system) c. Tropic hormone: when the secretion of one hormone causes secretion of another hormone Pancreas: functions as an exocrine & endocrine gland Exocrine function through digestive enzymes - For example how it secretes digestive juices into the duodenum as well as sodium bicarbonate to neutralize pH from acid that comes from the stomach Endocrine function through insulin and glucagon a. Insulin (a peptide hormone)→ secreted from the pancreas from beta islet cells (dots of cells distributed around the pancreas) brings glucose levels down in the bloodstream - Insulin is secreted (from beta islet cells) when glucose & sugar levels rise in the blood - Once insulin is secreted → it causes glucose uptake by body cells, glucose conversion to glycogen & stored in the liver, and glucose conversion to fat, ALL to maintain a level of glucose in the bloodstream (homeostasis) - Beta islet cells have: a. A glucose transporter in the plasma membrane that takes up glucose & increases the glucose concentration inside the cell → when the cell takes up more glucose it eventually leaves the mitochondria as produced ATP b. Have an ATP sensitive potassium channel (ion channel) that is closed if there is stress from the increased glucose → if there is no stress then the ATP levels in the cell will be higher. This ion channel has the same potassium gradient (-70 millivolts) because it has a sodium potassium pump - When glucose gets taken up, more ATP is in the cell which causes the ATP to block the ion channel & binds to a subunit that shuts the channel off which leads to depolarization until it hits a threshold for voltage dependent sodium & calcium channels to activate & flow in - How do the beta islet cells decide to secrete insulin? In response to elevated glucose levels in the bloodstream - ALSO, if we haven't eaten we could become hypoglycemic and the hormone glucagon brings the glucose level back up  - Diabetes: a common disease 1. Type 1 (usually in young people) → when the immune system thinks that the beta islet cells are foreign & so are targeted until the beta islet cells are removed → the only treatment is through insulin injection because there are no beta islet cells. 2. Type 2 → glucose levels are high due to genetic components, abundance of food, lack of exercise, stress & so on. The treatment for this is the drug called sulphonylureas that blocks potassium channels by dealing with the subunit SUR b. Glucagon → Is secreted in the pancreas by alpha islet cells when glucose levels go down meaning that it increases blood glucose levels - Alpha islet cells release glucagon into the bloodstream causing: the liver to break down glycogen to release glucose to the blood & as glucose level rises, the release of glucagon diminishes Hypothalamus & Pituitary Glands: master hormones secreting glands because the brain interfaces (interacts) with the endocrine system - The hypothalamus synthesizes hormones that are then stored in the pituitary glands… 1. Integrates nervous & hormonal responses 2. Synthesizes antidiuretic hormone (ADH) & oxytocin - ADH will reduce the loss of water if you are dehydrated & can be fooled by alcohol - Oxytocin is a reproductive hormone that is synthesized in the hypothalamus but is stored in the posterior pituitary gland 3. Releases factors causing hormone secretion by anterior pituitary - Anterior pituitary stores: the growth hormone, FSH, LH, Endorphins and enkephalins (both natural opiates), ACTH (involved with the Adrenal Cortex) - Thyroid Gland: located in neck region - What it does: 1. Secretes thyroxine (T4) & Tri-iodothyronine (T3) both of which are derived from tyrosine - These hormones contain iodine (a required micronutrient but also a risk factor if there were a nuclear event which can lead to thyroid cancer due to radioactive iodine in the air BUT an iodine supplement before the event is best to avoid absorbing it from the air) - Function → they increases basal metabolic rate in the body 2. T3 + T4 increase causes increases in blood pressure, body heat, & weight loss by stimulating metabolism - A hyperactive thyroid gland (when the body speeds up body metabolism) secretes more hormones & cause issues which has to be treated carefully → Graves disease 3. Secretes calcitonin which lowers calcium (Ca2+) levels in the blood (when its high) - If calcium is high → calcium deposit in bones (it is stored there) - Inhibits calcium absorption (in the intestine) - Inhibits calcium reabsorption (in the kidney) 4. Parathyroid glands have receptors that sense when calcium levels are low & secrete parathyroid hormone (PTH) that raises blood calcium level - Osteoclasts degrade bone matrix to release calcium into the interstitial fluid - Stimulates calcium absorption (intestine) - Stimulates calcium reabsorption (kidney) - High calcium level in blood inhibits PTH release Connection/ Balance: master hormones + thyroid gland 1. The hypothalamus wants to ramp up the metabolism & releases thyrotropin releasing hormone (TRH) - Negative feedback from T3, T4, & TSH to reduce the release of TRH in the hypothalamus if there is overall a lot of T3 & T4 2. TRH then communicates with the anterior pituitary to release thyroid stimulating hormone which is released in our brain and into the bloodstream 3. Then TSH reaches thyroid to release T3 & T4 Pineal Gland: located in the brain 1. Secretes melatonin - Light exposure → melatonin release inhibited (keeps us awake) - Dark exposure → high melatonin causes us to be sleepy 2. Older age = lower melatonin levels Adrenal Glands: sits on top of the kidneys 1. Adrenal Medulla secretes epinephrine (adrenaline/ hormone) - Functions the fight or flight response: a. Increase in blood pressure  b. Increase in heart rate c. Increase in glucose supply d. Increase in muscle contraction e. Stress signal from the nervous system - In the adrenal medulla there are cells full of adrenaline that contain vesicles & if the brain senses danger → action potentials are sent to the adrenal medulla and synapses are formed → At the synapse, a neurotransmitter is released called acetylcholine in the cells of adrenaline that depolarize & fire action potentials, then calcium flows in & the vesicles release to dump adrenaline into the bloodstream: 1. Neurons release acetylcholine that fire action potentials 2. Acetylcholine in chromaffin cells in the adrenal medulla cause depolarization 3. Depolarization of chromaffin cells cause action potentials & activate depolarization-activated calcium channels 4. Cytoplasmic calcium increase causes exocytosis of vesicles & release of adrenaline into the bloodstream 2. Adrenal Cortex (outside the adrenal medulla) → ACTH secreted by anterior pituitary in response to stress - ACTH causes secretion of corticosteroids - Cortisone increase causes increased: a. Blood glucose b. Glucose synthesis in liver c. Mobilize fats for energy d. Protein synthesis e. Suppression of immune system - The adrenal cortex also secretes aldosterone Lecture 16: Hormones II Chemical classes: 1. Steroid hormones → are hydrophobic & can pass through a lipid membrane to enter cells - Proteins/carriers bind to hydrophobic proteins & help them become solubilized in the blood or in body cells 2. Amines (soluble) → derived from amino acids usually tyrosine (small molecules such as epinephrine = adrenaline/not encoded by genes) 3. Peptide: amino acid chains, insulin, glucagon, ADH (all encoded by genes) 4. Other compounds such as prostaglandin (synthesized from fatty acids) Mechanism of hormone action: Signal transduction a. Lipid soluble hormones (steroids): - Pass through membranes - Enter all cells - Exert effects only if cells have receptor - Ex. progesterone, aldosterone, cortisone, testosterone, estrogen (all membrane permeable hormones that cat on specific targets when there is a receptor) How it works: 1. Hydrophobic hormones bind to a receptor protein which activates the receptor 2. Together they permeate into the next membrane through pores to get into the nucleus 3. Then it binds to DNA and directly activates gene expression 4. Then the new protein from the gene expression ends up in the cytoplasm b. Water soluble hormones: - Bind to specific membrane surface receptors - Turn on intracellular second messenger cascade - Regulates cell metabolism How it works: - receptors have a receiving domain on the extracellular side of the cell & at least one hydrophobic transmembrane domain, then an intracellular domain that signals to the cell & turns on a signal transduction once a hormone is present 1. Reception → A hormone from the extracellular fluid binds to a transmembrane receptor (the hormone is unique & needs a specific receptor) - Outside the cell there could be stimulatory or inhibitory hormones (accelerator & brakes are everywhere in biology) 2. Transduction → in the intracellular side this signals through coupling proteins that activate the next protein & so on - The proteins are G proteins (GTP = GDP + P) - The G protein can activate an enzyme that becomes the 2nd messenger producer (for the 2nd messenger inside the cell) Example: adenylate cyclase is the 2nd messenger producer that was specifically targeted and cyclic AMP is the second messenger - The 2nd messenger activates protein kinase regulation & phosphorylation - Other second messengers: a. Phospholipase C → an enzyme lipase that degrades phospholipids which are the most common lipids in the membrane (contains two nonpolar fatty acid chains & a polar/hydrophilic head group) by removing the polar head group  1. The second messenger is IP3 or triphosphate, the head group that is able to diffuse through cell & binds to/activates a IP3 gated calcium channel in the endoplasmic reticulum membrane 2. Now that calcium is released, they bind to target proteins like calmodulin to activate various proteins, then the cellular response b. Cyclic-AMP → produced by adrenaline in cells & activated protein kinase A c. Cyclic-GMP → degraded in the human visual system but in some cells a G protein coupled receptor can activate it its production from GTP d. Ca2+ → a second messenger like in muscle contraction & because it causes instant secretion e. IP3 → a second messenger f. Diacyl-glycerol (membrane) → the fatty acid chains (after phospholipase C) reaching into the membrane & its also a second messenger that activates a different protein kinase 3. Response → Activation of a cellular response inside the cell Example: This example is showing that signal transductions happens because a tiny hormone concentration causes a huge amplification Diversity of specificity: - Depends on the type of cell that is regulated by the hormone & receptor MEANING that the effect of a hormone on a cell will vary depending on the specific type of cell involved - Protein kinases with many specific kinases with active sites - Diversity such as slight mutations in structure a. Stimulus site and target site b. Many permutations of signaling cascade Tyrosine Kinase receptors: receptors for growth factors - Good for amplification by stimulating 3 kinases in a row that cause cell division response (which is present in cancer so not so good) Lecture 17: Immunity Inflammatory (innate immune) Response: - The first response is an inflammatory response (such as when a splinter punctures the skin) - The capillary walls become more permeable - Phagocytosis → eating of bacteria (the green is the bacteria) Complement cascade → mechanism that punctures holes in foreign invaders/bacteria 1. Antibodies (present in body fluids) recognize foreign antigens and the binding sites (2) on the antibody recognizes the antigen/protein as foreign & binds to it on the membrane of the bacterium 2. Once a sufficient of antibodies have binded to the bacteria, a complement protein from the circulatory system is attracted & attaches itself to the antibodies that have already binded to the invaders (more specifically, the antigens on the bacterium, invaders as a whole) - Complement proteins are only active once they attach to the antibodies that are already binded to the foreign antigens 3. Then the complement proteins release their proteins, punch a hole in the bacterium, & finally lyses it (which is the breakdown of a cell caused by damage to its plasma outer membrane) - If a big enough hole is made in the membrane, it will kill the cell 4. A pore (hole) is formed in the cell Macrophage & Neutrophils → A type of white blood/phagocytic/immune cell that surrounds and engulfs + degrades bacteria & dead cells - Macrophages engulf antibody-coated cells and non-antibody-coated cells Adaptive immune response → when there is a specific invader & the immune system is adapted to get it - Mediated by white blood cells/lymphocytes - Is very slow against infections at first (because this is the beginning, then after the antibody concentration increases & memory B-cells are set, its faster)  - Humoral immunity → antibody response where the B-cells produce antibodies that kills free bacteria & viruses - Cell-mediated immunity → mediated by cytotoxic T-cells that destroy cells infected intracellularly - Helper T cells → CD4 + T-cells which is important for regulation and activation of immune response Antibody Production: - Antigen → a foreign molecule (can be a protein or polysaccharide) that generate antibody production - Antibodies → “tag” antigen for engulfment by macrophage & bind to the antigen that can further activate a complement protein - Plants do not produce antibodies Humoral immunity: 1. B-cells produce antibodies 2. Each B-cell produces a single type of antibody - There are over 10 million different B-cells that are ready to recognize unique structures to produce antibodies 3. Immature B-cells expresses antibody on its cell surface (meaning that the B-cell has antibodies on it) - The antibodies on the cell look for foreign antigens/structures 4. Binding of specific antigen leads to B-cell activation - When an antigen binds to the antibody on the B-cell, signal transduction occurs in the B-cell - The signal activates the B-cell and allows it to reproduce/create clones of the cell with that specific antibody & it starts dividing into large clones groups of either memory B-cells and plasma cells (the plasma cells toss off the antibodies into the fluids of the body) - immune response will be faster, stronger, and more prolonged - memory can last for decades Cell-Mediated Immunity: infected cells need to be sacrificed - Intracellular parasites reproduce inside cells MEANING that viruses have the ability to enter our cells & infect them + reproduce inside them - T-cells (cytotoxic cells) recognize infected cells by… 1. First, an infected cell has antigen fragments inside 2. Every cell in our body has a Class 1 Major Histocompatibility complex protein (MHC) on the surface that presents antigens from inside the cell to a T-cell - Class 2 MHC are found only on surfaces of B-cells, T-cells, & macrophages → they bind to the antigen & present it BUT the T-cell receptor will not bind to the class 2 MHC(meaning it will not kill it) → instead it will bind to Helper T-cell (CD4+) through the receptor - Interleukin 1 is present when the Helper T-cell is in contact with the antigen & it activates specific helper T-cells to divide & grow into many helper T-cells with the same receptors - Then the Helper T-cell sends out a chemical (Interleukin 2) that amplifies the cytokines that stimulate the immune system to produce an immune response through cytotoxic T-cells (produce killer cells) & B-cells (produce plasma cells in this case) 3. The T-cell receptor on the cytotoxic T-cell (aka CD8+) recognizes the antigen attached to the class major histocompatibility complex protein (MHC) 4. Then the T-cell receptor binds to the antigen attached to the MHC & a hook from the cytotoxic T-cell comes around to holds onto the MHC as a support to kill the infected cell 5. The T-cell then releases perforins that punch holes into the infected cell → now it has pores/ has been lysed 6. Now the infected cell is less likely to survive/multiply & then a macrophage will come along to engulf it/remove it from the system - Cancer immunology → they try to turn off the inhibitory signal so that the immune system can attack the cancerous cell without the cancer cell trying to stop that from happening (because its your own cell) RNA vaccines: play a role in genetic issues & activate cellular & humoral immunity - Advantages: superior design, production speed, lower cost of production, & induction of both T-cells and B-cells - Disadvantage: require cold storage before distribution Lecture 18: Reproduction Male system: a. Male Gonad: Testes (gamete production) 1. Seminiferous Tubules → sperm formation during puberty & continues after that 2. Interstitial cells → testosterone production (reproductive hormone) b. Control by hormones: Embryonic (Testes → testosterone → induces primary male reproductive organs) Role of brain: - The hypothalamus produces & releases a Gonadotropin hormone (GnRH) that triggers the release of other hormones from the anterior pituitary that are FSH (follicle stimulating hormone) & LH (luteinizing hormone) - The FSH stimulates the production of sperm (spermatogenesis) & the LH targets androgen production (testosterone) that leads to primary & secondary sex characteristics (hair growth, etc.) - If testosterone levels are too high, there is a negative feedback that goes to the anterior pituitary & brain so that its not produced as much Female system:  a. Female Gonad: Ovaries (gamete production) 1. Oocytes (pre-stage eggs that will develop into the egg) → 400 thousand per ovary at birth - Arrested as diploid oocytes before meiosis (because in order to be fertilizable they have to become haploid) - 1 oocyte matures per cycle which starts during puberty 2. Follicles → 1 oocyte per follicle - Protects and controls the egg cell development - Maturation is when 1 follicle matures - Ovulation → egg is expelled from follicle into oviduct to uterus (Same as male…) → The hypothalamus produces & releases a GnRH that triggers the release of hormones from the anterior pituitary that are FSH (stimulates the follicle growth for ovulation/pre-ovulatio) & LH (stimulates androgen production) - Positive feedback loop → when only estrogen increases (estrogen going up controls the menstrual cycle) - Negative feedback loop → when both estrogen and progesterone increase at the same time Ovarian/menstrual cycle: about 28 days in a human cycle a. Ovarian cycle in the ovary: 1. Follicular phase - FSH stimulates the growth of a follicle - Growing follicles secrete estrogen into the bloodstream - Estrogen stimulates GnRH release in the hypothalamus - Steep increase in FSH & LH due to the positive feedback - Estrogen causes endometrium thickening (meaning that it prepares the uterus for the arrival of a fertilized egg) 2. Ovulation due to high levels of LH - Follicle breaks open & ovulation occurs - Triggers a change in the follicular layer into a hormone secreting gland that produces estrogen & progesterone (now both of these hormones increase) - LH causes the follicular tissue to form corpus luteum 3. Luteal phase - LH causes the corpus luteum to secrete estrogen & progesterone causing further development of endometrium (fluid nutrition for embryo) - Together estrogen & progesterone inhibit the hypothalamus GnRH & anterior pituitary (FSH + LH) - The negative feedback becomes dominant if egg fertilization has not occurred - Then the LH decreases so it causes the corpus luteum to degrade meaning that estrogen & progesterone secretion goes down, endometrium degenerates (causing menstruation), & low estrogen + progesterone causes FSH increase stimulation of new growth follicles) Then the cycle repeats… b. Menstrual cycle 1. Menstrual flow phase 2. Proliferation phase 3. Secretory phase Zygote development: Egg migration: ovary → oviduct → uterus Hormonal control: Chemical contraception: - Synthetic estrogen & progesterone - LH decreases - FSH decreases - No follicle growth - No ovulation Hormones after fertilization: - Embryo blastocyst (a ball of cells that forms early in a pregnancy after a sperm fertilizes an egg) secretes human chorionic gonadotropin (HCG) into the bloodstream that is detected in a pregnancy test - Corpus luteum sustains progesterone production and the levels stay high (replaces LH because of the negative feedback) due to the HCG - No menstruation - Progesterone controls pregnancy events - After 2 months, the placenta secretes its own progesterone to maintain the pregnancy & endometrium - Oxytocin causes uterine smooth muscle contractions during childbirth Lecture 19: Development Fertilization: - The egg has a protective layer called the vitelline membrane/layer 1. Contact: - The sperm makes contact with the jelly coat outside the vitelline layer & needs to get past it through a vesicle (called acrosome) packed with enzymes that can degrade the jelly coat 2. Acrosomal reaction: - The acrosome fuses with the plasma membrane of the sperm cell & releases hydrolytic (degradation) enzymes to get through it (degrades the jelly coat) 3. Growth of acrosomal process: - The plasma membrane of the sperm will be pushes towards the vitelline layer by actin filaments - Acrosomal process bind to protein (bindin) receptors on the vitelline layer which breaks open the vitelline layer 4. Fusion → occurs when the sperm head receptors (fun fact: Izumo) bind to the female receptors (fun fact: Juno) - The haploid nucleus (sperm) enters the cell at the plasma membrane/past the vitelline layer - Then Na+ channels open in egg membrane that cause depolarization of the whole egg - They don't have the saloon door deactivation gate meaning that the egg stays depolarization for about a minute - longer depolarization causes Polyspermy (fertilization by many sperm) to be blocked rapidly (1 sec to 1 min which is called the fast block) →  because multiple sperms fertilizing one egg is bad because it leads to abnormal development or miscarriage due to additional amount of chromosomes 5. Entry of sperm nucleus: - Nucleus of sperm enters the egg 6. Cortical reaction: - There are millions of vesicles at the plasma membrane that do exocytosis to secrete cortical granules that then secrete substances to create a hardened fertilization shell so that other sperm cells can’t fertilize it - Cortical granules build a hard layer surrounding the egg plasma membrane for protection (the sperm is already inside) 1. Gamete fusion causes calcium release from the endoplasmic reticulum 2. Cytoplasmic calcium increase causes cortical granules fuse with the plasma membrane and releases enzymes 3. Vitelline membrane lifts off causing slow block to polyspermy 4. Vitelline layer forms hardened fertilization membrane 1 min after 7. Activation of egg: - Calcium increases → metabolic rate increases - Protein synthesis from RNA - Fusion of egg and sperm nuclei after 20 minutes - DNA duplication & cell division after 90 minutes in sea urchin (36 hours in humans) Early development: Cleavage → morula → blastula → gastrula 1. Cleavage → cell division until you have a ball of cells (morula) 2. Morula → ball of cells 3. Blastula → a cavity called blastocoel forms on the inside of the morula 4. Gastrula: a. Gastrulation → rearranges the cells (germ cells) of a blastula into a 3-layered embryo called gastrula with a primitive gut - Organogenesis → the process in which various regions germ layers develop into organs: 1. Ectoderm → forms the outer layer - Skin + sweat glands & hair follicles, epithelial lining of mouth & anus, cornea & lens of eye, nervous system, sensory receptors in epidermis, adrenal medulla, tooth enamel, and epithelium of pineal & pituitary glands. 2. Endoderm → lines the embryonic digestive tract - move inward & open up a pore called the blastopore - Epithelial lining of digestive tract & respiratory system, lining of urethra, urinary bladder, & reproductive system, liver, pancreas, thymus, thyroid & parathyroid glands. 3. Mesoderm → fills the space between the endoderm & ectoderm - Skeletal & muscular system, muscular layer of stomach & intestine, excretory system, circulatory & lymphatic system, reproductive system (except germ cells), dermis of skin, adrenal cortex. a. Mammalian development: - 1st cell division = 36 hours - 2nd cell division = 60 hours - 3rd = 72 hours - After 5 days, over 100 cells b. Determination & differentiation: - Fate map → early in embryonic development cells of blastula may be predetermined to develop into special parts of the embryo - Determination → cells may be predetermined before differentiation meaning that developmental fate of cells is determined several stages before differentiation - Differentiate → specific genes (or sets of genes) are turned on given rise to specific functions - Homeobox genes regulate the development of entire segments of the body → they code for transcription factors (a protein that binds to dna and turns on specific genes) that regulate the transcription of other genes & has a major responsibility for the development of a particular region