L25- Electrical signaling 2

• Each subunit (VGCK) or domain (VGCNa) contains 6 transmembrane α-helices, S1-S6

• S_ contains the “voltage sensor”

• S5-S6 line ___

• S4 contains the voltage sensor

  • 4 sensors per channel

• S5-S6 line the pore

  • pore aas are polar/charged bc wanna create safe space for ions to go through lipids

Why might changes in voltage impact protein structure

Voltage gated channel reg domain includes

• inactivating particle which inserts into channel→ blocks

  • unstruc intracellular loop bw domains 3 + 4

• Selectivity (K+ Na+=key) det. by size of central pore + position of O2 atoms (lock)

  • Ionic radius K+ ≅ 0.138 nm

  • Ionic radius Na+ ≅ 0.102 nm

  • If “lock” is right shape for ”key”, then O outcompete H2O in ion hydration shells

Toxins that impact VGCs

• Pore blockers→ small molecules that bind + block the pore

  • ex) tetrodotoxin (puffer fish)

• peptidic gating modifier toxins→ peptides that bind + lock channel in a particular conformation

  • lock in open or closed→ loss of dynamic regulation

    • ex) spider venom

Ligand gated channel structure

• ex) The nicotine acetylcholine receptor

• Ligand (acetylcholine) gated Na+ channels

  • channel opens, Na+ goes into cell through diffusion Vm more positive towards 0→ membrane depolarizes

• 5 transmembrane protein subunits→ heteropentameric complex

  • 2x a subunits= ligand binding site-β, δ, γ subunits

• Each subunit has 4 transmembrane a-helices, M1-M4

• 2 binding sites for acetylcholine (a-subunit)

acehtylcholine receptor is a key link bw

• the brain and muscles

• so blocking this signal can lead to paralysis

• Cobra venom, nicotine, venome are neutrotoxins that covalently bind tightly + specifically to AchR

  • prevents it from being let go cause receptor to be open permanently

What process is important for dynamically regulating sigalling

• exocytosis

What factors impact how much current will flow

• Electrical potential

  • potnetial for electrical charge (ions) aka voltage to move

  • if low, less current (less ion flow) vice vera

• Electrical conductance

  • Ability of electrical charge to move across distance

Vm depends on

• Ion gradients (diffusion→ potential to move)

• Ion permeability (channels→ ability to move)

What is action potential

• a brief reversal of resting membrane potential

• Inside of neuronal membrane becomes + charged, compared to outside (flipped)

Outline what happens when ligand binds

• Permability of Na increases bc ligand gated Na+ channel opens

• Na+ flows into cell

• Vm rises toward 0 (less negative)→ depolarized cell membrane

• Voltage gated channels now open

Incremental changes in potential are called

• post synaptic potentials (PSPs)

  • one ligand-gated Na+ channel opening not enough to depolarize a cell

• Can be excitatory or inhibitory postsynaptic potentials (ESP/IPSP)

  • Excitaroty→ depolarization (Na+ in)

  • inhibitory→ hyperpolarizing (K+ out)

How to trigger a receiving neuron to undergo an action potential

• large # of EPSPs must be recieved

Temporal integration

• if multiple small influxes of Na+ occur from same postsynaptic terminal, 1 right after another

  • these small depolarizations build + summate

Spatial integration

• If an influx of Na+ occurs from multiple nearby postsynaptic terminals

  • these small depolarizations build + summate

If depolarization reaches a critical value (threshold) and if it doesnt what happens

• reaches threshold= action potential

• DOES NOT reach threshold= no action potential

• All or nothing

Outline the action potential

• Ligand binds→ channels open→ Na+ IN

  • threshold reached→ ACTION

• Depolarization= voltage gated channels opening→ more Na+ in

• Positive feedback loop= hodgkin cycle

• Permeability of Na+ increases→ ligand gated Na+ channel opens

• Membrane depolarizes

• VGC Na open so Na+ floods in→ Vm Reverses (+) → VGC Na closes

• Vm (+) now→ VGC K open (permeability of K+ increases)

• K+ floods OUT of cell→ hyperpolarization (overshoot)

• Membrane repolarizes→ back to resting equilibrium

(somewhere here the particle blocks Na from coming in when open channel)

Action potential phases

1. Depolarizing phase

• VGC Na open→ Na+ flux in, ACTION at -40mV

• Membrane potential quickly rises to +40mV

2. Repolarizing phase

• Reversed polarity closes + inactivates VGC Na, OPENS VGC K

• Membrane potential slowly drops

3. Hyperpolarizing phase

• VGC K stays open, VGC Na stays closed (due to the gag)

• Membrane potential drops below resting (-75 mV)

4. Return to rest

• Vm stabilizes again at resting potential (-60 mV)

  • Na+/K+ pump pumps 3 Na+ out/2K+ in

  • requires ATP (moving against gradient)

During absolute and relative refractory periods

• Absolute→ cannot trigger another action potential

  • Na channels inactivated by inactivating particle (gag)

  • cannot be opened by depolarization

• Relative→ difficult to trigger another action potential

  • Na channels active (gag removed)

  • membrane hyperpolarized

  • K channels still open

Propagation of action potentials

• signal received at dendrites

• moves passively through cell body (change ion conc)

• Action potential starts at axon hillock increases [VGC]

  • depolarization of adjacent membranes like dominos

• ONLY MOVES 1 direction bc of inactivating particle

  • VGC Na cannot reopen behind action potential

The myelin sheath

• Discontinuous myelin sheath made of glial cells

• Breaks in myelin= nodes of ranvier

• Directs electrical potential down the axon

  • DECREASES conductivity of membrane

  • retain electric charge→ insulation

  • signal travel farther, faster

• Insulates axon, and assembles specialized molecular strucs at NoR