Cell Physiology Lecture Notes PDF

5th Lecture 2023 [email protected] 1  Major Topics Cont’ (Physiology of membrane transports) 2  Learning Objectives After This lecture, you should be...

5th Lecture 2023 [email protected] 1  Major Topics Cont’ (Physiology of membrane transports) 2  Learning Objectives After This lecture, you should be able to: ❖ Compare and contrast exocytosis with endocytosis and the three types of endocytosis ❖ Describe the ionic basis of Resting Membrane Potential ❖ Explain how an Action Potential is generated and its phases ❖ Describe how Action Potentials propagate ❖ Explain the role of Myelin in Action Potential propagation ❖ Describe how Myelin is formed and w h a t i s t h e i m p a c t of myelin on nerve cells ❖ Compare Local Potentials with Action Potentials 3  ❑ Primary active transport based on their structure and function can be classified into four main groups: 1. P-type ATPases 3. F-type ATPases 2. V-type ATPases 4. A-type ATPases 4  ABC (ATP-Binding Cassette) transporters: ABC transporters play a major role in the Resistance to chemotherapy. 1 P-glycoprotein 2 Chloride Channel involved in the excretion of toxins from cells the cystic fibrosis transmembrane conductance regulator, CFTR, Oligosaccharide chains NH2 NH2 R domain ATP binding domains ATP binding domains 5  Agonist The cystic fibrosis transmembrane Membrane conductance regulator, CFTR is an ATP-gated Receptor anion channel with two remarkable distinctions: o First, it is the only ABC transporter that is an G ion channel AC ATP ADP o Second, CFTR is the only ligand-gated PKAa channel that consumes its ligand (ATP) ATP cAMP during the gating cycle— PKAj Genetic defects of CFTR lead to CF (Cystic fibrosis) disease. lack of ion control → Cell death in the lung’s epithelial → death of people with CF. 6 Mutations affecting the Dysfunction of active transport driven by ATP hydrolysis cause several diseases. Copper ion transporters (ATP 7A and 7B) are essential to the homeostasis of copper contents in our body. Menkes disease (syndrome) is caused by mutations in genes coding for the ATP7A, leading to copper deficiency. ❖ Impaired intestinal transport of copper. o So, Copper accumulates at abnormally low levels in the brain, bones, skin & hair, and liver, but at higher-than-normal levels in the kidney and intestinal tissues. Characteristic findings include kinky hair, growth failure, and nervous system deterioration. 7 Wilsons disease: is a rare genetic disorder characterized by mutated ATP7B leads to copper accumulation in the kidney, brain, and cornea. Menkes and Wilson Diseases are caused by mutated copper ion transporters 8  What happens to the many macromolecules that are too large to enter or leave cells through channels or carriers? ❖ They move in and out of the cell with the aid of vesicles created from the cell membrane. Endocytosis Exocytosis ▪ Cells use the endocytosis process to import large molecules and particles ▪ Material leaves cells by the process known as exocytosis (a process that is similar to endocytosis running in reverse) 9  Vesicular Transport Extracellular material to be tackled by lysosomes is brought into the cell by Endocytosis 3 types Pinocytosis Phagocytosis All cells Specialized Receptor- cells mediated endocytosis 10  Three variations of Endocytosis (a) Phagocytosis, the cell (b) Pinocytosis, the (c) Receptor-mediated membrane surrounds the cell membrane endocytosis, the uptake of large particle and pinches surrounds a small substances by the cell is off to form an volume of fluid and targeted to a single type intracellular vacuole. pinches off, of substance that binds at ex, bacteria forming a vesicle. the receptor on the ATP-using process external cell membrane. Vesicle is pinched off Vesicle is pinched off by protein Dynamin by protein Clathrin 11 12  In ,a migrates to the Plasma Membrane, binds, and releases its Contents to the outside of the cell. 13  Passive transport Active transport Expenditure of energy mol. ( ATP ) No expenditure of energy molecules Can take place against conc. Gradient Takes place along conc., electrical, & pressure gradient Carrier may or may not be required Carrier is always required Rate is proportional to conc. difference Rate is proportional to the availability Passive Active of carrier & energy. (Vmax) 14 Electrochemical Gradients and Membrane Biopotential All the solutes of both ICF and ECF are Electrically Charged. ❖ For charged particles, movement across the membrane will be determined not only by their Concentration Gradients, but also by the Electrical Potential across the membrane. ❑ Therefore, to achieve equilibrium, both Diffusional and Electrical forces must be taken into account. ▪ Cellular function depends on the close regulation of intracellular concentrations of , , , and. is the major cation within cells, and dominates the extracellular fluid. mostly remain with Na+ in the extracellular fluid. Phosphate ions and Negatively Charged Proteins are the major anions of the intracellular fluid. 15  Electrochemical Gradients and Membrane Biopotential ❑ Negative ions line the inside of cell membrane & positive ions line the outside. o Overall, the body is electrically neutral: ✓ for every cation, there is a matching anion. Equal number of charges (+/-) in ECF or ICF o However, ions are not distributed evenly between the ECF and the ICF. 16 ❖ The membrane potential results from the separation of an electrical charge across a membrane. ❑ By convention, it is expressed as the inside of the membrane compared with the outside of the membrane. ▪ All living cells are in chemical and electrical disequilibrium with their environment. ▪ This electrical disequilibrium, or Electrical Gradient between the extracellular fluid and the intracellular fluid, is called the Resting Membrane Potential difference, or Membrane Potential for short. So, All Living Cells Have a Resting Membrane Potential. Dead cells do not have membrane potentials. 17  Exp; A cell membrane potential of −70 mV means that the inside surface of the cell membrane is 70 mV more negative than the outside surface of the cell membrane. ❖ Polarization is based on a charge separation, so any movement away from 0 mV is a hyperpolarizing change and any movement toward 0 mV is a depolarizing change. Exp; Movement from −70 mV to −55 mV is therefore a 15 mV depolarization. 18 The equilibrium potential for any ion at 37 °C (human body temperature) can be calculated using the Nernst Equation: 19 Cell Membranes Are Permeable to Multiple Ions 20 What is the basis of Resting membrane potential? ❖ Most cells in the human body are about 40 times more permeable to K+ than to Na+, and the resting membrane potential is about –70 mV ✓Differential distribution of ions across neuronal membrane ✓Selective permeability of the membrane to ions ✓Na+/K+ pump 21  Membrane Potentials: Signals Information is carried within and between neurons by electrical and chemical signals. Signals are generated by the opening or closing of ion channels Types of signals : graded potentials and action potentials Used to integrate, send, and receive information 22  Graded Potentials Transmission of the local Short-lived, local changes in membrane potential potential along the membrane is called Decrease in intensity with distance electrotonic conductance Their magnitude varies directly with the strength of the stimulus Sufficiently strong graded potentials can initiate action potentials 23 23 Action Potential 24 Ionic basis of Action Potential 25 Ionic Basis of Action Potentials PNa>>>>PK (500 to 1000 folds) PK>>PNa (50 to 100 folds) PK>>PNa ENa 0 mV -80 mV EK Time → 26 Voltage-gated Na+ channel both gates are voltage and time-dependent + Resting + + Depolarization (Activated) + + Repolarization (Inactivated) + 27 ACTION POTENTIAL INITIATION: sodium channel density at base of axon and channel gating kinetics create a trigger zone for large inward current 28 further increasing Na+ permeability and further depolarizing the membrane in a positive feedback cycle. 29 Voltage-gated K+ channel K+ channels have just one gate; n gate During the resting state, n gate is closed, When the membrane potential rises, n gate opens and allows increased potassium diffusion outward through the channel. After depolarization n gate is still closed. Because of the slight delay in opening of the K+ channels. During repolarization increase in potassium exit from the cell is simultaneous with decrease in sodium entry to the cell Voltage-gated K+ channel is responsible for returning the depolarized cell to a resting state after each nerve impulse. 30 1. Action potentials are triggered by Depolarization 2. A threshold level of depolarization must Absolute Refractory Period be reached in order to trigger an AP. 3. Action potentials are all-or-none events; Overshoot The event either goes to completion (if depolarization is above threshold) or doesn’t occur at all (if the depolarization is below threshold). Threshold Level 4. An action potential propagates without decrement throughout a neuron. The conduction speed of an action potential in a typical mammalian nerve fiber is about 10–20 m/sec, although speeds as high as 100 m/sec have been observed. 5. At the peak of the action potential, the membrane potential reverses sign, becoming inside positive. 6. After a neuron fires an action potential (AP), there is a brief period, called the absolute refractory period, during which it is impossible to trigger another AP. 31  Refractory period Nerve fibers cannot produce a 2nd AP immediately after a 1st AP, because during the falling phase of the AP: (1) inactivation of Na+ channels is maximal; (2) K current is very large and decreases slowly. => Absolute refractory period followed by a relative refractory period during which the threshold gradually returns to normal. Na+ Channel’s states start to active active Absolute Relative Refractory Refractory period period (Na+ channels recover from inactivation & K+ channels close). 32  Absolute Refractory Period ❖ Time from the opening of the Na+ activation gates until the closing of inactivation gates The absolute refractory period: ✓ Prevents the neuron from generating an action potential ✓ Ensures that each action potential is separate ✓ Enforces one-way transmission of nerve impulses Na+ channel K+ channel Na+ channel K+ channel activated inactivated 33  Relative Refractory Period The interval following the absolute refractory period when: Sodium gates are closed Potassium gates are open Repolarization is occurring Second AP Stronger stimuli need to fire an action potential inactivated activated inactivated inactivated 34  Myelin is an insulating layer, or sheath that forms around nerves. It is made up of 70% lipid, 30% protein, with high cholesterol and phospholipid. Similar to cell membrane – a good insulator ❖ Formed by Schwann cells in PNS and oligodendrocytes in CNS 35  Conduction of Action Potential In an unmyelinated axon, an AP will slightly depolarize the surrounding tissue Triggering an AP in the new area… which will slightly depolarize the surrounding tissue… etc. An AP will only travel one way, due to refractory periods APs are non-decremental. -they never get smaller 36  Conduction of APs In unmyelinated axons, the AP must be generated over and over along the entire length 37  Propagation of action potentials in myelinated axons Myelin increases conduction velocity by increasing membrane resistance and lowering the membrane capacitance (12 m frog myelinated axon conduction velocity = 25 m/s, same as squid giant axon 30x greater in diameter). Capacitance is the ability to store electrical charge. In myelinated axons, AP develops only at nodes of Ranvier, current ‘jump’ from one node to the next, and causes new AP to be generated there.. Each node has a high concentration of voltage-gated Na+ channels, which open with depolarization and allow Na+ into the axon 38  ❖ The jump of the action potential from node to node is called saltatory conduction, saltatory is a Latin word meaning leap, or jump. ❑ When depolarization reaches a node, Na+ enters the axon through open channels. ❑ At the nodes, Na+ entry reinforces the depolarization to keep the amplitude of the AP constant. ❖ AP speeds up again when the depolarization encounters the next node. 39  In myelinated axons, the AP can “jump” between myelin sheaths Ion channels open in “node of Ranvier” depolarize neighboring node of Ranvier. Voltage-gated ion channels in the second node will open and generate an AP AP can move quickly across internodes, saves metabolic energy 40  Effect of Myelin on Neuronal Size An unmyelinated neuron would have to be 83-times larger than a myelinated neuron to conduct at the same speed Imagine the impact this would have on brain size you would probably be walking on your hands with your ears evolved as limbs to assist locomotion…. Because of the large brain that you would have 41 ▪ Nerves relay information from the brain to the body and back, much like a wire through which electrons move. ▪ When a wire loses part of its plastic covering it causes electrons stop flowing. ▪ When the myelin sheath is damaged, the “message” is lost as it hits this scared myelin. 42 Demyelinating diseases In the central and peripheral nervous systems, the loss of myelin slows the conduction of action potentials. Multiple sclerosis It is characterized by a variety of neurological complaints: ✓ Fatigue ✓ muscle weakness ✓ difficulty walking ✓ and loss of vision. Guillain-Barré syndrome 43 Factors that affect the action potential Local anesthetic Neurotoxins agents Ion channel Alteration in function [K+]o Alteration in [Ca2+]o 44 The relationship between extracellular fluid K+ levels and the conduction of action potentials is one of the most clinically significant. An increase in blood K+ concentration—hyperkalemia {hyper = above + kalium = potassium + -emia = in the blood}—shifts the resting membrane potential of a neuron closer to threshold and causes the cells to fire action potentials in response to smaller graded potentials. If blood K+ concentration falls too low—a condition known as hypokalemia— the resting membrane potential of the cells hyperpolarizes, moving farther from the threshold. This condition shows up as muscle weakness because the neurons that control skeletal muscles are not firing normally. Hypokalemia and its resultant muscle weakness are one reason that sports drinks supplemented with Na+ and K+ were developed. 45 When people sweat excessively, they lose both salts and water. If they replace this fluid loss with pure water, the K+ remaining in the blood is diluted, causing hypokalemia. By replacing sweat loss with a dilute salt solution, a person can prevent potentially dangerous drops in blood K+ levels. 46 Comparison of local (graded/subthreshold) potential and Action potential 47  Next lecture Intercellular communication: Synapses and signaling 48 Thanks for listening