Lecture 2. Excitability and ionic transport

Transcription

1 Lecture 2 Excitability and ionic transport

2 Selective membrane permeability: The lipid barrier of the cell membrane and cell membrane transport proteins Chemical compositions of extracellular and intracellular fluids.

3 Cell membrane and its selective permeability TRANSPORT OF SUBSTANCES THROUGH THE CELL MEMBRANE 1.Diffusion -Simple diffusion: - lipid-soluble subst. (O2, CO2, alcohols) through intermolecular spaces of the lipid barrier - through a membrane opening - protein channels (e.g., water, lipid-insoluble molecules that are water-soluble and small enough): selective permeable channels non-gated OR gated (open/closed by gates) voltage-gated ligand-gated (chemical-gated) -Facilitated diffusion = carrier mediated diffusion e.g. transport of most of aminoacids and glucose Driving force of diffusion and net diffusion depends on: -Substance availability, kinetic energy, membrane permeability -Concentration difference/gradient -Membrane electrical potential effect on diffusion of ions 2.Active transport - Primary active (pumps) - Secondary active (co- and counter-transport)

4 Simple diffusion through protein channels: Pores/channels are integral cell membrane proteins that are always open Pore diameter, its shape and its internal electrical charge/chemical bonds provide selectivity Aquaporins = water channels (13 different types) - protein pores which permit rapid passage of water through cell membranes but exclude other molecules (a narrow pore permits water molecules to diffuse through the membrane in single file). The pore is too narrow to permit passage of any hydrated ions.! Density of aquaporins (e.g., aquaporin-2) in cell membranes is not static but is altered in different physiological conditions.

5

6 Membrane ionic transport system (MITS) 1 - Ion channels 2 - Ion pumps 3 - Ion exchangers, carriers, co/counter transporters

7

8

9 1. Ion channels Gated (active) Ion Channels - Voltage gated - Ligand gated - Mechanic gated Non-gated (passive) Ion Channels The diversity of ion channels is significant, especially in excitable cells of nerves and muscles. Of the more than 400 ion channel genes currently identified in the human genome, about 79 encode potassium channels, 38 encode calcium channels, 29 encode sodium channels, 58 encode chloride channels, and 15 encode glutamate receptors. The remaining are genes encoding other channels such as inositol triphosphate (IP3) receptors, transient receptor potential (TRP) channels and others.

10 Gated (active) Ion Channels

11 The voltage-gated Na + channel - used in the rapid electrical signaling - components: - ion selectivity filter for Na+: Na+ discard the water molecules associated with them in order to pass in single file through the narrowest portion of the channel - activation gate that can open and close, as controlled by voltage sensors, which respond to the level of the membrane potential - inactivation gate limits the period of time the channel remains open, despite steady stimulation. a subunit: polypeptide chain of >1800 am.ac. embedded in cell membrane. * Nonpolar side chains coil into transmembrane alpha-helices and face outward where they readily interact with the lipids of the membrane. * By contrast, the polar peptide bonds face inward, separated from the lipid environment of the membrane. b subunit: anchor the channel to the plasma membrane - activation: - at resting membrane potential ( mv) the channel is closed; - the voltage sensor moves outward and the gate opens if any factor depolarize the membrane potential sufficiently (threshold ~ -50 mv).

12

13 Voltage-gated Na+ channel

14 Gated (active) Ion Channels Ligand-gated ion channels : ionotropic vs metabotropic Ionotropic - directly gate ion channels Metabotropic - indirectly gate channels via 2 nd messengers

15 Ligand-gated ion channels - glutamate receptors: - NMDA & AMPA ionotropic receptors - metabotropic group I & II receptors (G-prot. coupled) PCP- phenylciclidine

16 extracellular Gated (active) Ion Channels Mechanic gating ion channel Anchoring situs Cell membrane intracellular Fibrillary protein gate

17 Non-gated (passive) Ion Channels K + leak channels

18 2. Ion Pumps Functional particularities: -active transport of ions and organic molecules against concentration gradient - involve enzymatic reactions, ATP consume -decreased transport rate Ex: Na + /K + pump, H + pump, Ca 2+ pump...

19 3. Ion Exchangers/ Carriers/Cotransporters - Na/Ca - Na/H - Na/HCO 3 - Cl/HCO Na/K/2Cl - K/Cl, etc - Na/ aa, Na/Glucose

20 Ion gradients, channels, and transporters in a typical cell (Boron, 2009)

21 Factors that influence the resting membrane potential The Na + /K + pump contributes to resting membrane potential in 2 ways: Pumping Na + & K + ions in a 3:2 ratio contribute to internal electronegativity Maintaining a high K + concentration in the cell s interior The membrane conductance to K + far exceeds that to Na + : K + leakage results in internal electronegativity

22 When the neuron is inactive, the membrane is said to be at rest and has a resting membrane potential When the neuron is active, the flow of information is from soma to axon terminal action potentials (AP). A Motor Neuron

23 Membrane responses to stimulus current Hyperpolarizing currents produce responses 1 and 2. A small depolarizing current produces response 3. These are all graded local responses which dissipate locally. A sufficiently large current (threshold) produces an action potential (4), which can be propagated along the axon. Animation at

24 -A stimulus initiates a membrane electrical change that depend on the passive properties of the neuronal membrane -Electrical signal /potentials are initiated by local current flow -Local potentials then spread electrotonically over short distances, and decay with distance from their site of initiation (as some of the ions leak back out across the cell membrane and less charge reaches more distant sites); Considering the Ohms law and a stable membrane resistance, the diminished current with distance away from the source results in a diminished voltage change.

25 - When the potential is equal/over threshold, it propagates over a long distance - at the axon hillock level, the potential initiates an action potential (AP) that propagates without changing its amplitude - APs depend on a regenerative wave of channel openings and closings in the membrane

26 Action Potential (AP) nerve impulse = action potential: cycle of depolarization & repolarization needs no direct energy all-or-none principle The action potential is essential to our understanding of nervous system function. Its shape, velocity of conduction, and propagation fidelity are essential to the timing, synchrony, and efficacy of neuronal communication. G. J. Kress and S. Mennerick / Neuroscience 158 (2009)

27 Action Potential -The necessary actor in causing both depolarization and repolarization of the nerve membrane during the action potential is the voltage-gated Na+ channel -A voltage-gated K+ channel also plays an important role in increasing the rapidity of repolarization of the membrane. -These two voltage-gated channels are in addition to the Na + -K + pump and the K + -Na + leak channels. Na + permeability increases x

28 The nerve action potential Profile of a Nerve Action Potential Threshold -Occurs when Na + entering exceeds K + leaving -A rise in potential of mv is required The All-or-None principle An action potential will not occur until the initial rise in membrane potential reaches threshold. However any larger stimulus produces no greater response than that produced by the threshold stimulus, i.e., the threshold stimulus produces the maximal effect the action potential.

29 The nerve action potential Resting Stage Depolarization Stage Repolarization Result of Voltage-gated Na+ channels After-Hyperpolarization Membrane is polarized i.e., a 90 mv membrane resting potential present Membrane becomes very permeable to Na+ ions Influx of Na+ ions Polarized state is neutralized Potential merely approaches in smaller CNS fibres Membrane potentials overshoots beyond zero in large fibres Na+ channels get inactivated Permeability to K+ increases K+ channels remain open after repolarization

30 Cation conductances during an action potential action potential Ion conductance Na + conductance increases faster and lasts for a shorter duration. K + conductance is delayed, increases slowly and lasts longer

31 Membrane Refractoriness Refractoriness = non-responsive state Involves Na channel inactivation Absolute refractory period (ARP)- membrane is not responsive to any stimulation Relative refractory period (RRP) - membrane is responsive to supra-threshold stimuli

32

33 Na channels distribution and generation of AP in axon hillock The soma membrane has few Na+ channels it is harder to have sufficient Na+ influx to change membrane potential to the threshold potential (-45 mv). A voltage change up to +30 mv is required Axon hillock membrane has 7x more Na+ channels than the soma membrane and the threshold potential is lower (a voltage change of only mv is required to bring the membrane potential to threshold) = trigger zone for AP Action potentials in postsynaptic neurons are initiated at the axon hillock.

34 AP generation and conductance along the axon - initial depolarization at the axon hillock +f.b. for Na + channels critical membrane potential = threshold (all-or-none response) -AP: depolarization and repolarization, followed by afterhyperpolarization, as Ca2+-dependent K+ channels remain open and membrane permeability for K+ is higher - propagation of AP to the axon terminals synapses - also backpropagation in the soma & dendrites, without regenerating in the somal membrane, as somal membrane has too few Na + channels to regenerate APs; also, inactivation of Na channels at axon hillock (here, refractory period). -Speed of propagation depends on axon diameter & presence of myelin sheath -in unmyelinated axons, Na & K voltage-gated channels are uniformly distributed AP as a traveling wave -large diameter axons allow a grater flow of ions grated length of the axon to be depolarized increase of the conduction velocity -in myelinated axons, myelin sheath insulate the axon membrane generation of AP between the myelinated segments, at the nodes of Ranvier saltatory conduction

35

36 Propagation of impulses from the axon hillock Once the action potential begins, the potential travels forward along the axon and usually also backward toward the soma. However it does not regenerate in the soma membrane. Why is regeneration impossible in the soma membrane? EPSPs arrive and an AP is generated at the axon hillock. The AP is regenerated forward to the axon, depolarization spreads backwards to soma and dendrites, but impulse potential decays dies because the somal membrane has too few Na+ channels to regenerate APs.

37 Saltatory Conduction current flows electronically to the next node action potentials are regenerated only at nodes action potential jumps from node to node

38 Propagation of an Action Potential

39 Action Potential travels along the membrane as a wave of depolarization. Directional propagation of an AP