BM1 Physiology Lecture Notes 2024 PDF

BM1 physiology BATCH 2028  A word of caution—this document is of utmost secrecy. It would be wise to keep this information to yourself. Trust me, some things are best kept between us. Wishing you the best of luck on your adventures! May fortune smile...

BM1 physiology BATCH 2028  A word of caution—this document is of utmost secrecy. It would be wise to keep this information to yourself. Trust me, some things are best kept between us. Wishing you the best of luck on your adventures! May fortune smile upon you! BATCH 2028 TABLE OF CONTENTS 01 Homeostasis Cellular Transport & Transport 02 Mechanism 03 Signal Transduction Membrane Potentials & 04 Nerve Conduction 05 Synaptic Transmission 06 Muscle Physiology Bone Physiology and 07 Calcium Homeostasis 08 Autonomics PHYSIOLOGY LECTURE HOMEOSTASIS Dr. Vincent Mari Angelo W. Laguardia | August 1, 2024 HOMEOSTASIS OUTLINE I. HOMEOSTASIS………….……………….….….1 II. HOMEOSTATIC CONTROL SYSTEMS….…..1 A. BASIC PRINCIPLES IN HOMEOSTATIC CONTROL SYSTEMS……………………1 1. FEEDBACK REGULATION……......2 2. FEEDFORWARD REGULATION….2 III. COMPONENTS OF HOMEOSTATIC CONTROL SYSTEMS……….………………....2 IV. PROCESSES RELATED TO HOMEOSTASIS…………………………………3 REFERENCES Dr. Laguardia PPT & Lecture Guyton and Hall 14th Edition HOMEOSTATIC CONTROL SYSTEMS HOMEOSTASIS A control system made up of a collection of interconnected components, which maintain a - Refers to the maintenance of the steady state physical or chemical parameter of the body of the internal environment. relatively constant. - A dynamic process defined as a state of reasonably stable balance between BASIC PRINCIPLES IN HOMEOSTATIC physiological variables. CONTROL SYSTEMS Walter Cannon - Coined the term ‘homeostasis’ 1. Stability of an internal environment variable is brought about by a balance between inputs Aristotle and outputs. - Good health was associated with a balance 2. In negative feedback, a change in the variable among the multiple life-sustaining “forces” being regulated brings about responses that (humors) in the body. tend to move the variable in the direction Claude Bernard opposite the original change. - A constant internal environment is a prerequisite for good health. 1 of 3 PHYSIOLOGY LECTURE HOMEOSTASIS Dr. Vincent Mari Angelo W. Laguardia | August 1, 2024 3. Homeostatic control systems cannot maintain FEEDBACK REGULATION complete constancy of any given feature of the internal environment. 1. Negative feedback - An increase or decrease in a variable brings about responses that tend to move the variable in the direction opposite to the direction of the original change - Most common control mechanism regulating hormone release 4. The set point of some variables regulated by homeostatic control systems can be reset. 2. Positive feedback - An initial disturbance in a system sets off a train of events that increase the disturbance even further 5. It is not always possible for every variable to be maintained within a narrow normal range in response to an environmental challenge. There is a hierarchy of importance. FEEDFORWARD REGULATION Anticipates changes in a regulated variable/parameter, thus improving the speed of the body’s homeostatic responses, and minimizing fluctuations in the level of the variable/parameter regulated. Ex.: Compensatory responses are activated before the colder temperature outside can cause the internal temperature to fall. COMPONENTS OF HOMEOSTATIC CONTROL SYSTEMS Reflexes - Specific, involuntary, unpremeditated, built-in responses to a particular stimulus 2 of 3 PHYSIOLOGY LECTURE HOMEOSTASIS Dr. Vincent Mari Angelo W. Laguardia | August 1, 2024 Biological Rhythms Mechanisms that enable homeostatic mechanisms to be utilized immediately and automatically by activating them at times when a challenge is likely to occur but before it does actually occur. These are rhythmic changes in body functions such as waking and sleeping, hormone concentrations in the blood, excretion of ions in the urine, and body temperature regulation. Local homeostatic responses - Responses initiated by a change in the external or internal environment, and they induce an alteration of cell activity with the net effect of counteracting the stimulus. PROCESSES RELATED TO HOMEOSTASIS Adaptation Refers to the ability to respond to a particular environmental stress Acclimatization Refers to the ability to respond to a particular environmental stress upon prolonged exposure to that stress. 3 of 3 PHYSIOLOGY LECTURE CELLULAR TRANSPORT AND TRANSPORT MECHANISM Dr. Vincent Mari Angelo W. Laguardia | August 1, 2024 CELLULAR TRANSPORT & The cell membrane consists entirely of a lipid TRANSPORT MECHANISM bilayer with large numbers of protein molecules in the lipid, many which penetrate all the way through the membrane OUTLINE This layer is not capable of being mixed with the ECF & ICF I. CELL MEMBRANE ……………………………...1 This serves as a barrier against movement of water molecules and water soluble substances. II. DIFFUSION ……………………………………….2 However, lipid-soluble substances can diffuse A. DIFFUSION THROUGH THE CELL directly through the lipid substance MEMBRANE………………………………2 Membrane Protein Molecules B. DIFFUSION THROUGH PROTEIN - interrupt the continuity of the lipid bilayer PORES AND CHANNELS-SELECTIVE - serves as an alternative pathway through the PERMEABILITY & “GATING” OF cell membrane CHANNELS……………………………… 3 1. Transport proteins C. FACILITATED DIFFUSION………….…. 4 2. Channel proteins D. FACTORS THAT AFFECT NET RATE - have free watery spaces all OF DIFFUSION…………………………..4 the way through the molecule E. OSMOSIS ACROSS SELECTIVELY and allow free movement of PERMEABLE MEMBRANES—“NET water, as well as selected ions DIFFUSION” OF WATER ……………….4 or molecules 1. OSMOLARITY…………………..….5 3. Carrier proteins - bind with molecules or ions III. PRIMARY ACTIVE TRANSPORT……………...5 that are to be transported where, conformational IV. SECONDARY ACTIVE TRANSPORT…………6 changes take place in the protein molecules, which then V. ACTIVE TRANSPORT THROUGH CELLULAR move the substances through SHEETS………………………………………..….7 the interstices into the other REFERENCES side of the membrane Guyton and Hall 14th Edition Channel and Carrier proteins are usually selective for the types of molecules or ions OUTL which are allowed to cross the membrane. CELL MEMBRANE 1 of 8 PHYSIOLOGY LECTURE CELLULAR TRANSPORT AND TRANSPORT MECHANISM Dr. Vincent Mari Angelo W. Laguardia | August 1, 2024 b. through intermolecular spaces Diffusion vs. Active Transport without interaction with carrier proteins in the membrane. The Rate of diffusion is determined by: a. amount of substance available b. the velocity of kinetic motion c. the number and sizes of openings in the membrane Simple diffusion can occur through the cell membrane by two pathways: a. the interstices of the lipid bilayer if the Diffusion diffusing substance is lipid- soluble ○ is a random molecular movement of b. through watery channels that substances molecule by molecule via: penetrate all the way through some of a) intermolecular spaces in the the large transport proteins membrane 2. Facilitated Diffusion b) in combination with a carrier protein - requires interaction of a carrier protein ○ the energy that causes diffusion is the energy which aids passage of molecules or of the normal kinetic motion of matter ions through the membrane by binding chemically with them and shuttling them through the membrane in this Active Transport form is movement of ions or other substances across the membrane in combination with a carrier protein Diffusion of Lipid- Soluble Substances Through The carrier protein causes the substance to move the Lipid Bilayer against an energy gradient, from low- concentration state to high concentration state. Lipid Solubility movement requires additional source of energy - is an important factor for determining how besides kinetic energy rapidly it diffuses through the lipid bilayer Oxygen, nitrogen, carbon dioxide, and alcohols are highly lipid soluble, and can dissolve directly in the DIFFUSION lipid bilayer and diffuse through the cell membrane The rate of diffusion of each of these substances The constant motion of molecules and ions in the through the membrane is directly proportional to body fluids is what physicists call “heat” its lipid solubility. The motion of these particles is what physicists call “heat”— the greater the motion, the higher the Diffusion of Water and Other Lipid- Insoluble temperature—and the motion never ceases, Molecules Through Protein Channels. except at absolute zero temperature. This continual movement of molecules among one Water is highly insoluble in the membrane lipids, another in liquids or gases is called diffusion. and readily passes through channels in protein molecules that penetrate all the way through the DIFFUSION THROUGH THE CELL MEMBRANE membrane. Aquaporins Has 2 Subtypes: - protein pores in the cell that selectively permit 1. Simple Diffusion rapid passage of water - kinetic movement of molecules or ions - highly specialized occurring through: - are at least 13 different types in various cells a. a membrane opening of mammals. 2 of 8 PHYSIOLOGY LECTURE CELLULAR TRANSPORT AND TRANSPORT MECHANISM Dr. Vincent Mari Angelo W. Laguardia | August 1, 2024 Other lipid- insoluble molecules can pass through the protein pore channels in the same way as water molecules. DIFFUSION THROUGH PROTEIN PORES AND CHANNELS- SELECTIVE PERMEABILITY & “GATING” OF CHANNELS Substances can move by simple diffusion directly along these pores and channels from one side of the membrane to the other Pores are composed of: Integral cell membrane proteins- that form open tubes through the membrane and are always open. However, It’s diameter of a pore and its electrical charges provide selectivity that permits only certain molecules to pass through Example: aquaporins permit rapid passage of water through cell membranes but exclude other molecules. They have a narrow pore that permits water molecules to diffuse through the membrane in a single file. ✓ SODIUM CHANNELS: 2 IMPORTANT CHARACTERISTICS OF - 0.3 to 0.5 nanometer in diameter, but the ability PROTEIN CHANNELS of sodium channels to discriminate between other (1) selectively permeable to certain competing ions in the surrounding fluids is crucial substances; for proper cellular function. (2) Can be opened or closed by gates that - The narrowest part of the sodium channel’s open are regulated by electrical signals (voltage- pore, the selectivity filter, is lined with strongly gated channels) or chemicals that bind to the negatively charged amino acid residues. channel proteins (ligand- gated channels). - These strong negative charges can pull small (1) Selective Permeability of Protein Channels dehydrated sodium ions away from their hydrating -highly selective for transport of one or more water molecules into these channels, although the specific ions or molecules ions do not need to be fully dehydrated to pass -selectivity results from specific characteristics through the channels. of the channel: diameter, shape, and the nature - Sodium ions diffuse in either direction according of the electrical charges and chemical bonds to the usual laws of diffusion. along its inside surfaces. ✓ POTASSIUM CHANNELS: - permit passage of potassium ions across the cell membrane about 1000 times more than sodium ions - potassium channels were found to have a tetrameric structure consisting of four identical protein subunits surrounding a central pore - pore loops (At the top of the channel pore), form a narrow selectivity filter. Lining the selectivity filter are carbonyl oxygens. 3 of 8 PHYSIOLOGY LECTURE CELLULAR TRANSPORT AND TRANSPORT MECHANISM Dr. Vincent Mari Angelo W. Laguardia | August 1, 2024 Gating of Protein Channels molecules or positive ions smaller than this diameter to pass through. FACILITATED DIFFUSION It is also known as carrier-mediated diffusion. Substances are transported across the cellular membrane with the help of carrier proteins. It differs from simple diffusion because it has a maximum rate of diffusion known as Vmax. As the substrate concentration increases, diffusion rate will only reach a maximum of Vmax. FACTORS THAT AFFECT NET FATE OF DIFFUSION Concentration Difference ○ The concentration increase of a substance on one side of the membrane is proportional to the rate of diffusion across the concentration gradient - Provides a means of controlling ion ○ The rate equation is shown as follows: permeability of the channels. Net diffusion ∝ (Co − Ci) - The opening and closing of gates are Electrical Difference - “Nernst Potential” controlled in two principal ways: ○ An electron potential applied to the membrane (1) Voltage Gating causes ions to diffuse through the membrane (2) Chemical (Ligand) Gating even if no concentration difference exists ○ Negative ions are attracted to applied positive (1) VOLTAGE GATING charges while positive ions are attracted to - The molecular conformation of the gate or its applied negative charges chemical bonds responds to the electrical ○ The Nernst equation determines the electrical potential across the cell membrane. difference that will balance with the - This process is the basic mechanism for eliciting concentration difference of univalent ions (e.g. action potentials in nerves that are responsible for Na+ ions) at normal body temperature (37°C): nerve signals. 𝐶1 - Figure 4-5,the potassium gates are on the EMF (in millivolts) = ±61log 𝐶2 intracellular ends of the potassium channels, and they open when the inside of the cell membrane Pressure Difference becomes positively charged. ○ The pressure increase on one side of the membrane is proportional to the rate of (2) CHEMICAL (LIGAND) GATING diffusion, where solutes from the high pressure - opened by the binding of a chemical substance side diffuse to the low pressure side. (a ligand) with the protein, which causes a conformational or chemical bonding change in the protein molecule that opens or closes the gate. - ex: acetylcholine receptor which serves as a OSMOSIS ACROSS SELECTIVELY PERMEABLE MEMBRANES—“NET DIFFUSION” OF WATER ligand- gated ion channel. - Acetylcholine opens the gate of this channel, providing a negatively charged pore about 0.65 Osmosis is the movement of water across a nanometer in diameter that allows uncharged semipermeable membrane from an area of high 4 of 8 PHYSIOLOGY LECTURE CELLULAR TRANSPORT AND TRANSPORT MECHANISM Dr. Vincent Mari Angelo W. Laguardia | August 1, 2024 water concentration to an area of low water concentration. Osmotic pressure is the amount of pressure required to stop osmosis. ○ The number of particles per unit of fluid volume matters more in osmotic pressure rather than mass. Osmolality is an expression of the concentration of a solution based on the number of particles. ○ 1 gram of the molecular weight of an osmotically active solute pertains to 1 osmole. ○ 300 milliosmoles per kilogram of water is considered as the normal osmolality level of extracellular and intracellular fluids. Actual osmotic pressure in body fluids is 0.93 times the theoretical calculation because ions of opposite charges (e.g. Na+ and Cl-) tend to attract Figure 4-12 shows the basic physical one another. components of the Na+-K+ pump The carrier proteins that penetrate through the cell membrane where the transport depends OSMOLARITY on is composed of two subunits: a. ą subunit (MW 100,000) Osmolar concentration expressed as osmoles per b. β subunit (MW 55,000) liter of solution rather than osmoles per kilogram of The larger protein ą subunit has specific water. features that are important for the functioning of the pump: PRIMARY ACTIVE TRANSPORT 1. It has three binding sites for sodium ions on the portion of the protein that protrudes to the inside of the cell. In primary active transport, the energy is 2. It has two binding sites for potassium derived directly from the breakdown of ions on the outside. adenosine triphosphate (ATP) or some other 3. The inside portion of this protein near high- energy phosphate compound. the sodium binding sites has Sodium- potassium (Na+- K+) pump adenosine triphosphatase (ATPase) ○ A transporter that pumps Sodium Ions activity. Out of Cells and Potassium Ions into When two potassium ions bind on the outside Cells of the carrier protein and three sodium ions ○ It is responsible for maintaining the bind on the inside, the ATPase function of the sodium and potassium concentration protein becomes activated. differences across the cell membrane, Activation of the ATPase function leads to as well as for establishing a negative cleavage of one molecule of ATP, splitting it to electrical voltage inside the cells. adenosine diphosphate (ADP) and liberating a high- energy phosphate bond of energy. The liberated energy cause a chemical and conformational change in the protein carrier molecule, extruding three sodium ions to the outside and two potassium ions to the inside. The Na+-K+ ATPase pump can run in reverse. If the electrochemical gradients for Na+and K+ are experimentally increased to the degree that the energy stored in their gradients is 5 of 8 PHYSIOLOGY LECTURE CELLULAR TRANSPORT AND TRANSPORT MECHANISM Dr. Vincent Mari Angelo W. Laguardia | August 1, 2024 greater than the chemical energy of ATP outside of the cell. The other pumps hydrolysis, these ions will move down their calcium ions into one or more of the concentration gradients, and the Na+-K+ intracellular vesicular organelles of the pump will synthesize ATP from ADP and cell, such as the sarcoplasmic phosphate. reticulum of muscle cells and the therefore, the phosphorylated form of the mitochondria in all cells. Na+-K+ pump can either: ○ The carrier protein penetrates the ○ donate its phosphate to ADP to membrane and functions as an produce ATP enzyme ATPase, with the same ○ use the energy to change its capability to cleave ATP as the conformation and pump Na+ out of the ATPase of the sodium carrier protein. cell and K+ into the cell. ○ The difference is that this protein has a highly specific binding site for The Na+ -K+ Pump is Important for calcium instead of for sodium. Controlling Cell Volume ○ Without the pump, cells would swell Primary Active Transport of Hydrogen Ions and burst ○ Important at 2 places at in the body: ○ Inside the cell contains proteins and (1) in the gastric glands of the other organic molecules that cannot stomach; and escape. These are negatively charged (2) in the late distal tubules therefore, potassium, sodium, and and cortical collecting ducts of other positive ions attract. All these the kidneys molecules and ions then cause osmosis of water to the interior of the Energetics of Primary Active Transport cell. Unless this process is checked, ○ The energy required is proportional to the cell will swell indefinitely until it the logarithm of the degree that the burst. substance is concentrated, as ○ This mechanism pumps 3 Na+ ions to expressed by the following formula: the outside of the cell for every 2 K+ ions pumped to the interior. ○ The Na+- K+ pump performs a continual surveillance role in SECONDARY ACTIVE TRANSPORT maintaining normal cell volume. In secondary active transport, the energy is Electronic Nature of the Na+ - K+ Pump derived secondarily from energy that has been ○ the Na+- K+ pump is said to be stored in the form of ionic concentration electrogenic because it creates an differences of secondary molecular or ionic electrical potential across the cell substances between the two sides of a cell membrane. membrane, created originally by primary active transport. In both cases, transport depends on Primary Active Transport of Calcium Loss carrier proteins that penetrate through the cell ○ Calcium ions are normally maintained membrane, as is true for facilitated diffusion. at an extremely low concentration in When sodium ions are transported out of cells by the intracellular cytosol of virtually all primary active transport, a large concentration cells in the body, at a concentration gradient of sodium ions across the cell membrane about 10,000 times less than that in usually develops, with a high concentration outside the extracellular fluid. the cell and a low concentration inside. This ○ This level of maintenance is achieved gradient represents a storehouse of energy, mainly by two primary active transport because the excess sodium outside the cell calcium pumps. One, which is in the membrane is always attempting to diffuse to the cell membrane, pumps calcium to the interior. 6 of 8 PHYSIOLOGY LECTURE CELLULAR TRANSPORT AND TRANSPORT MECHANISM Dr. Vincent Mari Angelo W. Laguardia | August 1, 2024 In counter- transport, sodium ions again attempt to diffuse to the interior of the cell because of their large concentration gradient. Co-Transport of Glucose and Amino Acids Along with Sodium Ions ○ Glucose and many amino acids are transported into most cells against large concentration gradients; the mechanism of this ○ Sodium- calcium counter- transport occurs action is entirely by co- transport. through all or almost all cell membranes, with sodium ions moving to the interior and calcium ions to the exterior; both are bound to the same transport protein in a counter-transport mode. ○ Sodium- hydrogen counter- transport occurs in several tissues. ○ An especially important example is in the proximal tubules of the kidneys, where sodium ○ The transport carrier protein has two binding ions move from the lumen of the tubule to the sites on its exterior side, one for sodium and interior of the tubular cell and hydrogen ions one for glucose. Also, the concentration of are counter- transported into the tubule lumen. sodium ions is high on the outside and low on the inside, which provides energy for the ACTIVE TRANSPORT THROUGH CELLULAR transport. SHEETS ○ A special property of the transport protein is that a conformational change to allow sodium At some parts in the body, substances must be movement to the interior will not occur until a transported all the way through a cellular sheet glucose molecule also attaches. instead of simply through the cell membrane. ○ Sodium- glucose co-transporters are especially important for transporting glucose Transport of this type occurs through the following: across renal and intestinal epithelial cells. ○ intestinal epithelium; ○ Sodium co- transport of amino acids occurs in ○ epithelium of the renal tubules; the same manner as for glucose, except that it ○ epithelium of all exocrine glands; uses a different set of transport proteins. ○ epithelium of the gallbladder; and ○ Other important co- transport mechanisms in ○ membrane of the choroid plexus of the brain, at least some cells include co- transport of along with other membranes potassium, chloride, bicarbonate, phosphate, The basic mechanism for transport of a substance iodine, iron, and urate ions. through a cellular sheet is as follows: ○ active transport through the cell membrane on Sodium Counter-Transport of Calcium and one side of the transporting cells in the sheet; Hydrogen Ions ○ either simple diffusion or facilitated diffusion ○ Two especially important counter- transporters through the membrane on the opposite side of (i.e., transport in a direction opposite to the the cell primary ion) are sodium- calcium counter- transport and sodium- hydrogen counter- transport. 7 of 8 PHYSIOLOGY LECTURE CELLULAR TRANSPORT AND TRANSPORT MECHANISM Dr. Vincent Mari Angelo W. Laguardia | August 1, 2024 Through these mechanisms, almost all nutrients, ions, and other substances are absorbed into the blood from the intestine. These mechanisms are also how the same substances are reabsorbed from the glomerular filtrate by the renal tubules. 8 of 8 PHYSIOLOGY LECTURE Signal Transduction Pathways Dr. Vincent Mari Angelo W. Laguardia | August 3, 2024 TRANSCRIPTION FACTORS - a class of SIGNAL TRANSDUCTION proteins which act as gene switches, interacting in a variety of ways to activate or OUTLINE repress the initiation process that takes place at the promoter region of a particular gene I. SIGNAL TRANSDUCTION PATHWAYS RESPONSIVE ELEMENT - a specific A. General Classes of Hormones…………...1 regulatory (promoter) sequence of the DNA B. Receptor Based on their Associated that either activates or represses transcription Mechanisms of Signal Transduction….…2 of specific genes and formation of messenger C. Binding of lipid-soluble RNA messengers to receptors…………………2 D. Binding to lipid-insoluble messengers to receptors ……………………….………3 Receptors that are ligand- gated ion channels……….............3 Receptors that function as Enzyme………………...................4 Receptors that interact with cytoplasmic JAK ……...................5 E. G Protein Activation …….........................5 G Protein coupled receptors.........6 G Protein coupled receptors with adenylyl cyclase....................6 G Protein coupled receptors via Phospholipase C...........................7 G Protein coupled receptors via Phosphodiesterase.......................7 F. Second Messenger Activation.................8 Calcium as second GENERAL CLASSES OF HORMONES messengers..................................8 Phospholipase C, DAG, IP3.........9 PROTEINS AND Hormones secreted by: G. Six steps in signaling events..................11 POLYPEPTIDES Anterior and Posterior Pituitary Gland [REFERENCES] Pancreas (insulin and Dr. Vincent Laguardia PPT & Lecture glucagon) Parathyroid Gland OUTL (parathyroid hormone) SIGNAL TRANSDUCTION PATHWAYS STEROIDS Secreted by: (FROM Adrenal Cortex (cortisol This refers to the diverse sequence of events CHOLESTEROL) and aldosterone) between receptor activation and cellular Ovaries (estrogen and responses. progesterone) Testes (testosterone) SIGNAL- is the receptor activation DERIVATIVES Secreted by: OF THE AA Thyroid (thyroxine and TRANSDUCTION- denotes the process by (TYROSINE) triiodothyronine) which a stimulus is transformed into a Adrenal Medulla response (epinephrine and norepinephrine). 1 of 11 PHYSIOLOGY LECTURE Signal Transduction Pathways Dr. Vincent Mari Angelo W. Laguardia | August 3, 2024 RECEPTORS BASED ON THEIR ASSOCIATED Mechanism: MECHANISMS OF SIGNAL TRANSDUCTION INTRACELLULAR/ NUCLEAR RECEPTORS Proteins located in the cytosol or nucleus that are ligand-activated transcription factors Link extracellular signals to gene transcription LIGAND-GATED ION CHANNELS/ IONOTROPIC RECEPTORS Integral membrane proteins Hybrid receptors or channels involved in signaling between electrically excitable cells CATALYTIC RECEPTORS Integral membrane proteins When activated by a ligand, these proteins are either enzymes themselves or part of an enzymatic complex G PROTEIN-COUPLED RECEPTORS Integral membrane proteins that work indirectly through an intermediary (G protein) to activate or inactivate a separate membrane-associated enzyme of channel BINDING OF LIPID-SOLUBLE MESSENGERS TO RECEPTORS Important points: More than one gene may be subject to control Generally act on cells by binding to by a single receptor type intracellular receptor proteins. ○ E.g., the adrenal gland hormone ○ E.g., Steroid hormones, Vitamin D cortisol acts via its intracellular Part of nuclear receptors receptor to activate numerous genes involved in the coordinated control of cellular metabolism and energy balance. Transcription of a gene or genes may be decreased rather than increased by the activated receptor. ○ E.g.,, cortisol inhibits transcription of several genes whose protein products mediate inflammatory responses that occur following injury or infection. 2 of 11 PHYSIOLOGY LECTURE Signal Transduction Pathways Dr. Vincent Mari Angelo W. Laguardia | August 3, 2024 the biochemical machinery inside the cell Protein kinase ○ phosphorylates other proteins by transferring a phosphate group to them from ATP. ○ Phosphorylation of a protein allosterically changes its tertiary structure and, consequently, alters the protein’s activity. Protein phosphatases ○ dephosphorylate proteins ○ serve to stop a signal once a cell response has occurred. Receptors that function as enzymes Receptors that are ligand-gated ion channels Receptors that interact with cytoplasmic Janus kinases Mostly polypeptide hormones ○ E.g., Norepinephrine, Epinephrine, FSH,LSH, etc. RECEPTORS THAT ARE LIGAND-GATED ION CHANNELS The protein that acts as the receptor is also an ion channel. When the receptor is activated by a first messenger (ligand), it undergoes a conformational change, opening a channel through the plasma membrane. BINDING OF LIPID-INSOLUBLE MESSENGERS TO RECEPTORS Ligand-Gated Ion Channels - these channels are termed "ligand-gated ion channels" Water-soluble messengers cannot pass freely because their opening is triggered by ligand through the membrane binding. Cannot enter the cells via lipid bilayer ○ They are prevalent in the plasma ○ It binds to extracellular portion of membranes of neurons and skeletal receptor protein embedded in the muscle. plasma membrane First messengers The opening of these channels leads to an ○ extracellular chemical messengers increase in net diffusion of specific ions across such as hormones or transmitters the plasma membrane, causing a change in Second messengers the cell's membrane potential. ○ enter or are generated in the ○ The change in membrane potential cytoplasm due to receptor activation represents the cell's response to the by the first messenger first messenger. ○ diffuse throughout the cell for chemical relays from the plasma membrane to Role of Ca2+ Channels - if the channel is a Ca2+ channel, its opening increases the 3 of 11 PHYSIOLOGY LECTURE Signal Transduction Pathways Dr. Vincent Mari Angelo W. Laguardia | August 3, 2024 cytosolic concentration of Ca2+, which is Some plasma membrane receptors for crucial in the transduction pathway for many water-soluble messengers have intrinsic signaling systems. enzyme activity, primarily functioning as protein kinases. Receptor Tyrosine Kinases (RTKs) - most receptors with intrinsic enzyme activity are receptor tyrosine kinases, which phosphorylate tyrosine residues. Activation Mechanism ○ Binding of a specific messenger causes a conformational change in the receptor. ○ This activates the receptor's enzymatic portion on the cytoplasmic side, leading to autophosphorylation of its own tyrosine residues. Docking and Signal Transduction ○ Phosphotyrosines serve as docking sites for cytoplasmic proteins. ○ These docking proteins bind and activate other proteins, initiating signaling pathways within the cell. ↓ ○ All these pathways commonly involve phosphorylation of cytoplasmic proteins. Exception: Receptor-Guanylyl Cyclase Some receptors act as both a receptor and a guanylyl cyclase, catalyzing the formation of cyclic GMP (cGMP). Role of cGMP ○ cGMP functions as a second messenger, activating cGMP-dependent protein kinase. ○ This kinase phosphorylates specific proteins to mediate the cell's response. Physiological Importance ○ These receptors are notably present in the retina, where they play a role in RECEPTORS THAT FUNCTION AS ENZYMES visual processing. ○ The pathway involving guanylyl cyclase is used by a limited number of messengers. Cytoplasmic Guanylyl Cyclase and Nitric Oxide (NO) ○ In some cells, guanylyl cyclase enzymes are cytoplasmic. ○ The first messenger nitric oxide (NO) diffuses into the cell and activates guanylyl cyclase, forming cGMP. ○ NO is produced from arginine by nitric oxide synthase, present in various cell types, including blood vessel lining cells. ○ NO acts locally to relax smooth muscle in blood vessels, aiding in 4 of 11 PHYSIOLOGY LECTURE Signal Transduction Pathways Dr. Vincent Mari Angelo W. Laguardia | August 3, 2024 blood vessel dilation and blood The result of these pathways is the synthesis pressure regulation. of new proteins, which mediate the cell’s response to the first messenger. ○ Ex. cytokines—proteins secreted by cells of the immune system that have a critical function in immune defenses. Mechanism: Binding of a water-soluble ligand to the receptor ↓ Changes in the conformation of the receptor activates the receptor ↓ Janus kinase is activated ↓ The activated JAKs phosphorylate different target proteins ↓ RECEPTORS THAT INTERACT WITH The synthesis of new proteins that are responsible for CYTOPLASMIC JANUS KINASES (JAKs) mediating the cell’s response to the initial signal G PROTEIN ACTIVATION This occurs when tyrosine kinase activity is not Bound to the inactive receptor is a protein present in the receptor itself but in a family of complex located on the cytosolic surface of the cytoplasmic kinase – Janus kinase (JAKs). plasma membrane and belonging to the family of proteins known as G proteins. The binding of a first messenger to the G proteins contain three subunits receptor causes a conformational change in a. Alpha-can bind GDP and GTP. the receptor that leads to activation of the b. Beta-help anchor the alpha subunit in janus kinase. the membrane. c. Gamma- same with beta The different janus kinases phosphorylate G protein serves as a switch to couple a different target proteins, many of which act as receptor to an ion channel or to an enzyme in transcription factors. the plasma membrane. These receptors are known as G-protein coupled receptors. 5 of 11 PHYSIOLOGY LECTURE Signal Transduction Pathways Dr. Vincent Mari Angelo W. Laguardia | August 3, 2024 The G protein may cause the ion channel to G-PROTEIN COUPLED RECEPTORS WITH open, with a resulting change in electrical ADENYLYL CYCLASE signals. The G protein may activate or inhibit the membrane enzyme with which it interacts. Such enzymes, when activated, cause the generation of second messengers inside the cell. Mechanism: A first messenger binds to the receptor ↓ Conformational change in the receptor ↓ Increased affinity of G protein’s alpha subunit for GTP ↓ When bound toGTP, the alpha subunit dissociates from the beta and gamma subunits ↓ The activation of the receptor by the binding of This allows the alpha subunit to link up with another the first messenger activates G protein, known plasma membrane protein - either ion channels or as the Gs (s = stimulatory). enzymes called plasma membrane effector proteins Activation of adenylyl cyclase. ↓ Catalyzes the conversion of cytosolic ATP to These proteins mediate the next steps in the sequence cyclic 3’,5’ - adenosine monophosphate or of events leading to the cell’s response cyclic AMP (cAMP) Cyclic AMP then acts as a second messenger that diffuses throughout the cell to trigger the sequence of events leading to the cell’s G PROTEIN COUPLED RECEPTORS ultimate response to the first messenger. cAMP is broken down to AMP, by the enzyme They consist of a single polypeptide chain cAMP phosphodiesterase. with: cAMP binds to and activates an enzyme ○ Seven membrane-spanning α-helical known as cAMP- dependent protein kinase, segments also called as protein kinase A. ○ An extracellular N terminus that is ○ This brings about a cell’s response glycosylated (secretion, contraction, and so on). ○ A large cytoplasmic loop that is Leads to “amplification cascade” of events composed mainly of hydrophilic amino that convert proteins in sequence form acids between helices 5 and 6 inactivate to active forms. ○ A hydrophilic domain at the ○ One active molecule of adenylyl cytoplasmic C terminus. cyclase may catalyze the generation of 100 cAMP molecules.. The 5,6-cytoplasmic loop appears to be the cAMP can phosphorylate to a large number of major site of interaction with the intracellular G different proteins. protein. The receptors for some first messengers, upon activation by their messengers, inhibit adenylyl cyclase. ○ This inhibition results in less generation of cAMP. Many cells express both stimulatory and inhibitory G proteins in their membranes, providing a means of tightly regulating intracellular cAMP concentrations. 6 of 11 PHYSIOLOGY LECTURE Signal Transduction Pathways Dr. Vincent Mari Angelo W. Laguardia | August 3, 2024 leading to the cell's response to the first messenger. ○ Ca2+ also helps in activating some forms of protein kinase C. These hormones act via certain G G-PROTEIN-COUPLED RECEPTORS VIA protein-coupled receptors. PHOSPHOLIPASE C Sometimes some hormones would act on either phospholipase c or the adenylyl cyclase pathways depending on the tissue where it is found G-PROTEIN-COUPLED RECEPTORS VIA PHOSPHODIESTERASE Gq is activated by a receptor bound to a first messenger. Activated Gq activates a plasma membrane effector enzyme called phospholipase C. ○ catalyzes the breakdown of a plasma membrane phospholipid known as Phosphatidylinositrol bisphosphate (PIP2) to diacylglycerol (DAG) and inositol triphosphate (IP3) DAG activates members of a family of related Phototransduction protein kinases known collectively as protein ○ A photon interacts with a receptor and kinase C, then phosphorylates a large number activates the G protein transducin of other proteins, leading to a cell’s response. ○ The at activates phosphodiesterase IP3 binds to receptors located in the (PDE) which in turn hydrolyzes cGMP endoplasmic reticulum. and lowers the intracellular ○ These receptors are ligand-gated Ca2+ channels that open when bound concentrations of cGMP to IP3. ○ and therefore closes the ○ The concentration of Ca2+ is greater cGMP-activated channels. in the endoplasmic reticulum in the cytosol, Ca2+ diffuses out of this The cellular concentration of cAMP can be organelle into the cytosol, significantly changed either by altering the rate of its increasing the cytosolic Ca2+ messenger-mediated synthesis or the rate of concentration. ○ This increased Ca2+ concentration its phosphodiesterase-mediated breakdown then continues the sequence of events 7 of 11 PHYSIOLOGY LECTURE Signal Transduction Pathways Dr. Vincent Mari Angelo W. Laguardia | August 3, 2024 ↓ SECOND MESSENGER ACTIVATION Diacylglycerol and Ca2+ activate protein kinase C at the surface of the plasma membrane. ↓ Phosphorylation of cellular proteins by protein kinase C produces some of the cellular responses to the hormone. CALCIUM AS SECOND MESSENGER When a chemical messenger binds with the receptor, instead of activating, it activates another messenger, which in turn, activates the cell’s overall response. ○ a messenger activated is called a second messenger. Ca2+ is maintained at very low concentration Cyclic nucleotides: in the cystosol ○ cAMP ○ Large electrochemical gradient favors ○ cGMP the diffusion of Ca2+ into the cell via Products of phosphoinositide breakdown: calcium channels found in the plasma ○ IP3 membrane and endoplasmic reticulum ○ DAG (mediated by IP3) usually as a Arachidonic acid metabolites response to a first messenger. Calcium Mechanism: Mechanism: Ca2+ channel in the plasma membrane opens in Hormone binds to a receptor response to first messenger (the receptor itself may ↓ contain the channel, or the receptor may activate a G The occupied receptor causes GDP-GTP exchange on protein that opens the channel) Gq ↓ ↓ Gq, with bound GTP, moves to PLC and activates it ↓ Cytostolic concentration of Ca2+ slightly increases due Active PLC cleaves phosphatidylinositol to entry of the aforementioned ions. 4,5-bisphosphate to inositol triphosphate (IP3) and diacylglycerol ↓ ↓ IP2 binds to a specific receptor on the Ca2+ binds to calcium channels in the endoplasmic Endoplasmic reticulum, releasing sequestered Ca2+ reticulum further releasing more Ca2+ into the cytosol. 8 of 11 PHYSIOLOGY LECTURE Signal Transduction Pathways Dr. Vincent Mari Angelo W. Laguardia | August 3, 2024 ↓ 4 Ca2+ attach to the binding site of calmodulin. ↓ Calmodulin changes shape and is activated ↓ Activated calmodulin activates enzymes, usually calmodulin-dependent protein kinases. ↓ Calmodulin-dependent protein kinases activate or inhibit the proteins resulting in a cellular response to the first messenger via phosphorylation. PHOSPHOLIPASE C, DAG, IP3 Mechanism: Phospholipase C degrades phosphatidylinositol 4,5-bisphosphate ↓ produce the second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol ↓ IP3 causes a transitory rise in intracellular free Ca2+, whereas DAG immediately activates protein kinase C. 9 of 11 PHYSIOLOGY LECTURE Signal Transduction Pathways Dr. Vincent Mari Angelo W. Laguardia | August 3, 2024 10 of 11 PHYSIOLOGY LECTURE Signal Transduction Pathways Dr. Vincent Mari Angelo W. Laguardia | August 3, 2024 SIX STEPS IN SIGNALING EVENTS MODULATION (MEMBRANE-ASSOCIATED RECEPTORS) Of the effector: ○ By enzymes ○ Ion channels ○ Cytoskeletal components ○ Transcription factors RESPONSE Of the cell to the initial stimulus Collections of actions representing the summation and integration of input from RECOGNITION multiple signaling pathways The same signaling molecule can sometimes TERMINATION bind to more than one kind of receptor The binding of a ligand to its receptor involves Response by feedback mechanism at any or weak, noncovalent interactions that all levels of signaling pathway. characterize substrate-enzyme interaction. ○ Between groups of opposite charge (ionic bonds) ○ Transient dipole in one atom generating the opposite dipole in an adjacent atom (Van der Waals interactions) ○ Between nonpolar groups (hydrophobic interactions) TRANSDUCTION Ligand Binding ↓ Conformational change in the receptor: Triggers catalytic activities Receptor interaction with membrane or cytoplasmic enzymes ↓ Generation of second messenger or catalytic cascade TRANSMISSION Of the second messenger’s signal to appropriate effector: ○ Activation of intracellular kinases and phosphates ○ Release of sequestration of intracellular ions ○ Regulation of metabolic pathways that generate ATP 11 of 11 PHYSIOLOGY LECTURE Membrane Potentials & Nerve Conduction Dr. Vince Laguardia | August 15, 2024 MEMBRANE POTENTIALS STRUCTURAL AND FUNCTIONAL DIVISIONS OF THE NERVOUS SYSTEM AND NERVE CONDUCTION OUTLINE STRUCTURAL DIVISIONS OF THE NERVOUS SYSTEM Central Nervous System (CNS) I. NERVE TISSUE…………………………………..1 Consisting of the brain and spinal cord A. STRUCTURAL AND FUNCTIONAL Overall command center, processing and DIVISIONS OF THE NERVOUS transmitting information throughout the body SYSTEM……………………………………1 Peripheral Nervous System (PNS) B. TYPES OF NEURONS……………………1 Composed of Nerves and Ganglia C. ANATOMICAL FEATURES……………….2 Receives and projects information to and from NERVE CELL BODY………….2 the CNS AXONS…………………………2 Mediates some reflexes DENDRITES…………………...2 D. AXONAL TRANSPORT PROCESSES….2 E. SUPPORTING CELLS……………………3 FUNCTIONAL DIVISIONS OF THE NERVOUS F. NERVE FIBERS…………………………...3 SYSTEM G. GANGLIA…………………………………..3 Sensory Division (afferent) H. NEURAL PLASTICITY & Somatic REGENERATION…………………………3 Sensory input perceived from eyes, ears, skin, and musculoskeletal II. MEMBRANE POTENTIALS…………………….4 system A. RESTING MEMBRANE POTENTIAL Visceral OF NEURONS……………………………..4 sensory input not perceived B. TRANSIENT CHANGES IN RESTING consciously e.g. from internal organs MEMBRANE POTENTIAL (RMP)............4 and cardio vascular structures GRADED POTENTIALS…………..4 Motor Division (efferent) ACTION POTENTIALS…………….4 Somatic Motor (somatic nervous system) PHASES OF ACTION Voluntary control of skeletal muscle POTENTIAL…………………………5 Autonomic Motor (Autonomic nervous system) PROPAGATION OF ACTION Involuntary control of cardiac muscle, POTENTIAL…………………………5 and glands C. VOLTAGE-GATED NA+ & K+ CHANNEL………………………………….6 SODIUM CHANNEL………………..6 TYPES OF NEURONS POTASSIUM CHANNEL…………..6 Structural Class D. REFRACTORY PERIODS………………..6 Neuron Structure and Location ABSOLUTE REFRACTORY Multipolar Neurons The most prevalent kind PERIOD……………………………….6 of neuron contains one RELATIVE REFRACTORY or more dendrites and PERIOD……………………………….7 one axon. E. NERVE CONDUCTION…………………..7 Bipolar Neurons one dendrite and one POINT-TO-POINT axon, consisting of the CONDUCTION…………………….7 sensory neurons of the SALTATORY CONDUCTION…….7 retina, the olfactory [REFERENCES] epithelium, and the inner Dr. Laguardia’s PPT & Lecture ear. Guyton and Hall 14th Edition Unipolar or it includes all other Pseudounipolar Neurons sensory neurons, each OUL having a single process that diverges close to NERVE TISSUE the perikaryon; the longer branch extends Nerve tissue is spread throughout the body, forming a toward the peripheral cohesive communication network. ending while the other branch toward the CNS 1 of 7 PHYSIOLOGY LECTURE Membrane Potentials & Nerve Conduction Dr. Vince Laguardia | August 15, 2024 Anaxonic Neurons They have a large axon may have which greatly affects the influence of number of dendrites but the cell. no real axons; they control the electrical The cell opposite the terminal receives these chemical messengers, or neurotransmitters, through diffusion across an extracellular gap. On the other hand, some neurons use a series of bulging areas called ANATOMICAL FEATURES varicosities along the axon to release their chemical messengers. CELL BODY The axons of many neurons are covered by sheaths of myelin, which usually consists of 20 to 200 layers of Also called the perikaryon/soma, the cell body highly modified plasma membrane wrapped around contains nucleus and surrounding cytoplasm exclusive the axon by a nearby supporting cell. In the CNS, for cell process. In contact with nerve endings from these myelin-forming cells are a type of glial cell called other neurons which convey excitatory or inhibitory oligodendrocytes. In the PNS, glial cells called stimuli. The large, euchromatic nucleus and Schwann cells form individual myelin sheaths well-developed nucleolus indicates intense synthetic surrounding 1- to 1.5-mm-long segments at regular activity. Has Nissl bodies, a basophilic region with intervals along some axons. The spaces between large masses of polysomes and a concentrated RER adjacent sections of myelin where the axon’s plasma which indicates a high rate of protein synthesis. membrane is exposed to extracellular fluid are called the nodes of Ranvier. Myelin sheath speeds up Components: Nucleus, Rough Endoplasmic Reticulum conduction of the electrical signals along the axon and (Nissl bodies), Mitochondria, Golgi Bodies, conserves energy. Neurofilaments, Microtubules, Lipofuscin. The neurofilaments which is a form of intermediate filament form conspicuous neurofibrils when exposed AXONAL TRANSPORT PROCESSES to silver stains while lipofuscin is an endogenous pigment deemed as a residual product of lysosomal digestion. Anterograde Transport driven by the motor protein kinesin moves essential materials like nutrients, DENDRITES enzymes, mitochondria, and neurotransmitter-filled vesicles from the perikaryon/cell body (soma) to the axon These are short, small branches emerging off the terminals soma; a series of highly branched outgrowths of the crucial for the neuron's metabolic activities and cell that receive incoming information from other for transmitting signals to other neurons or neurons. Branching dendrites increase a cell’s surface muscle cells at the synapse area increasing a cell’s capacity to receive signals from Retrograde Transport many other neurons through its knoblike outgrowths powered by the motor protein dynein carries materials from the axon terminals back called dendritic spines. to the cell body recycles membrane vesicles and transports AXON growth factors and signals that help the neuron adapt and maintain its structure however, it can also be a route for harmful The axon or nerve fiber is a long process that arises agents, like tetanus toxin and certain viruses, from the cell body which transports signals to the cells to enter the central nervous system it is intended for. The part of the axon that emerges from the cell body and is usually where electrical Both are vital for the proper functioning of neurons, ensuring that essential components are delivered signals originate is known as the initial segment, or where they are needed and that waste and signaling axon hillock. Collaterals are the branches that an molecules are effectively managed. 2 of 7 PHYSIOLOGY LECTURE Membrane Potentials & Nerve Conduction Dr. Vince Laguardia | August 15, 2024 SUPPORTING CELLS nerve impulse is nerve impulse is Neurons make up about half of the cells in the human disseminated thru disseminated thru point to CNS, while the other half are glial cells. Glial cells saltatory conduction point conduction provide physical and metabolic support to neurons and can divide throughout life, making them the source of Peripheral Nervous Central Nervous system many CNS tumors. system Central Nervous System (CNS) Glial Cells: Oligodendrocytes – it forms the myelin GANGLIA sheath around CNS axons, aiding transmission by myelination multiple axons. Ganglia are generally ovoid structures that house Astrocytes - It regulates the extracellular fluid neuronal cell bodies along with the glial satellite cells by removing potassium ions and that surround them. These are supported by a delicate neurotransmitters around synapses. It forms the blood-brain barrier by stimulating tight connective tissue framework and encased in a denser junctions between capillary cells for selective capsule. As relay stations for transmitting nerve filtering. Moreover, it sustains neurons by impulses, each ganglion has at least one nerve providing glucose and removing ammonia. It entering and another going out. The type of nerve guides neuronal migration in embryos and impulse passing through determines whether the stimulates growth with growth factors. Lastly, it ganglion functions as sensory or autonomic. possesses neuron-like properties, such as ion channels and neurotransmitter receptors, possibly contributing to brain signaling. SENSORY AUTONOMIC Microglia – it acts as immune cells in the GANGLION GANGLION CNS, performing functions similar to Lined by a distinct CT Less well-developed CT macrophages. capsule capsule Ependymal Cells – it is the line of fluid-filled Usually have a Often possess multipolar cavities in the brain and spinal cord which regulates the production and flow of pseudo-unipolar neurons cerebrospinal fluid. neurons Receives afferent Affects the activity of Peripheral Nervous System (PNS) Glial Cells: (sensory) impulses smooth muscles, Schwann Cells – it produces the myelin that proceed to the glandular secretion, sheath for the peripheral neuron axons, similar central nervous modulate heart rhythm to oligodendrocytes in the CNS. system and other unconscious activities NERVE FIBERS Does not harbor Contains synapses Nerves in the central nervous system contain axons synapses enclosed by sheaths of glial cells to facilitate axonal Does not use Uses acetylcholine as a function. On the other hand, axons are sheathed by acetylcholine chemical mediator Schwann cells or neurolemmocytes in the peripheral nerves. Depending on the diameter of the axons, it NEURAL PLASTICITY & REGENERATION may or may not form myelin around it. The myelin layers are very rich in lipids, providing insulation and Neural plasticity initiating action potential formation along axolemma. The nervous system exhibits neuronal differentiation and the formation of synapses Embryonic Development: Excess neurons are Myelinated Fibers Unmyelinated Fibers formed and those not forming correct synapses undergo apoptosis thicker axons which are axons of small diameter; Neurotrophins regulate the neural plasticity wrapped by myelin lacks myelin and reformation processes sheaths Neuronal stem cells Located among the cells of the presence of Nodes of no formation of Nodes of ependyma Ranvier Ranvier They produce neurons, astrocytes, and oligodendrocytes. 3 of 7 PHYSIOLOGY LECTURE Membrane Potentials & Nerve Conduction Dr. Vince Laguardia | August 15, 2024 Limitations: Fully differentiated CNS neurons cannot divide to replace lost cells. A potassium channel in the nerve membrane also Astrocytes: proliferation occurs at injury sites allows potassium ions to leak out of a resting cell. and can impede axonal regeneration Although these channels can also allow some sodium Peripheral Nerve Regeneration ions to leak, they are about 100 times more permeable Injured axons have a significantly higher to potassium than sodium. This difference in capacity for regeneration and functional permeability plays a crucial role in establishing the recovery. normal resting membrane potential. PNS can regenerate if the cell bodies are intact, and damaged. Axon Degeneration: Distal parts break down; TRANSIENT CHANGES IN RESTING MEMBRANE Schwann cells help by dedifferentiating, POTENTIAL (RMP) shedding myelin, and increasing. The beginning of regeneration is ma