Neurophysiology Flashcards
Transduction
-conversion of one form of energy into another
Fluid Mosaic Model
model of cell membrane
- phospholipids, proteins, ion channels
- lipid bilayer with embedded proteins
- proteins can be relatively fixed or mobile in the plane of the membrane, extracellular, intracellular, or spanning (channels & pumps)
Channels
- gated aqueous pores
- contain gates which control whether ions can traverse the pore (regulated by movements of part of the channel in response to the gating stimulus)
Control Mechanism of Gates
- transmembrane voltage
- binding of ligand
- temperature
- mechanical distortion of the membrane
Selectivity Filter
a part of the channels which determined which ion types can move through the channel
-narrow portion or a charged region in the pore
Internal Binding Sites
- allow modulation of channel function by signaling pathways
- association with other molecules may modulate channel function & channel localization can be controlled by anchoring to the cytoskeleton
Electrical Consequences of Cell Membrane Structure
- Ion Channels: resistive elements (conductors of ions)
- Lipid Bilayer: insulator (cf, dielectric of capacitor, stores charge)(capacitance) is RC circut
Ohm’s Law
V = IR
Resting Membrane Potential
- membranes are semi-permeable to ions
- at rest, neuronal cell membranes are primarily potassium permeable
- selective permeability results in separation of charge which results in a transmembrane voltage
Concentration of Ions Intra & Extracellularly
-Na+ out
-K+ in
-Cl- passively distribute across the membrane
RMP = -70mV
Nernst Equation
Eion = 61 log [ion]o / [ion]i o=outside, i=inside
Ena+ = +5-mV Ek+ = -100mV Ecl- = -60mV
Nernst Equation
- if membrane is at equilibrium & only permeable to a single ion species it can be described
- predict what the membrane potential would be if the membrane became permeable to only a single ion species
Ex = (RT)/(zF) lin [x]o/[x]i
Goldman-Hodgkin-Katz equation
-predicts the membrane potential at equilibrium when all permeant ion species are taken into account
Membrane ATP Driven Ion Pumps
Na+/K+ pump is an ATPase: 3Na+ out, 2K+ in
Ca-ATPase transports Ca2+ ions across the cell membrane
Complicated & Varied Cell Geometry
- distributed geometry, so not all membrane in the cell is isopotential at a given time
- signals propagate through the neuron
- passive RC properties of membrane set biophysical limits on this propagation of electrical signals
- Active mechanisms (voltage-gated channels) are superimposed on these passive, or electrotonic properties of distributed membranes
Electrotonic Signal Propagation
- passive movement of charge
- time constant is longer for a larger cable diameter
- amplitude decreases with distance
Hyperpolarizing
-events which enhance membrane potential - make the membrane more negative
Depolarizing
-stimuli which make the cell less polarized (less -, more +)
Large Depolarizing Stimuli
-cause a large, brief depolarization followed by repolarization (action potential), exceeded threshold of depolarization
Action Potential
- arge, brief depolarization followed by repolarization
- active response that is due to activation of voltage-gated ion channels
Threshold
the voltage at which inward (depolarizing) current is just balanced by outward (hyperpolarizing current)
- any further depolarization leads to the all-or-none AP response
- balance b/w Na+ current and outward K+ currrent
AP rising Phase
up-stroke
AP falling Phase
downstroke (restoration of the original membrane potential = repolarization)
afterhyperpolarizatoin (AHP)
- upon repolarization, membrane potential undershoots the original resting potential
- “undershoot”, due to an inc. K+ conductance relative to original resting potential (delay of opening of K+ channels relative to Na+ channels)
2 Major Types of Neural Electrical Signals
1) Graded Potentials
2) Action Potentials
Graded Potentials
- passive responses, amplitude of the response is proportional to the amplitude of the stimulus (linear relationship predicted by Ohm’s law)
- Examples: receptor potentials (due to stimulation of a sensory receptor) & synaptic potentials (due to synaptic transmission)
- analog response
- no threshold, decrement with distance, small
- not voltage sensitive, no refractory period
Action Potentials
- active responses (voltage-dependent)
- threshold, above which the amplitude of the response is sterotyped (all-or-none), large, brief
- digital response, regenerative
Ionic Basis for Action Potential: Upstroke
-due to an increase in membrane permeability of Na+
Ionic Basis for Action Potential: Downstroke
-due to inactivation of Na+ channels as well as activation of voltage-gated potassium channels
3 States of Channels
- Closed
- Activated (open)
- Inactivated
- controlled by transmembrane voltage
Channel state at hyperpolarized potentials?
negative to -60mV
- Na+ channels will be closed, will not conduct Na+ ions but are available to be activated by depolarization
- all will be opened at 0 (depolarized)
Activation
-process of going from the closed to open state
Deactivation
-process of going from opened state to closed state (if time the membrane is depolarized is brief (<1ms), the channels may transit back from the open to closed state)
Inactivation
- continued depolarization causes open channels to be inactivated
- process of going into teh inactivated state (possible to enter from closed state too)
- no ions are conducted through the channel and the channel is not available to be activated by another depolarization
Remove Inactivation
- transition from inactivated state to closed state
- a finite time at a negative membrane potential is required
- only after channels are back in closed state are they once again available to be activated
States for Repolarizing K+ channels
- no inactivation time, only closed and activated (open)
- resting potential: most are closed
- depolarization: more K+ are open (activation), process is slower than in Na+ channels and occur at relatively more depolarized potentials than Na+ channels (facilitate attainment of threshold and underlie the afterhyperpolarization)
- repolarization results in channel deactivation & re-entry into the closed state (deactivation)
Relative Refractory Period
- after AP, time period over which it requires a larger second stimulus to elicit another AP
- due to the increased K+ permeability (that often causes afterhyperpolarization) following the AP
Absolute Refractory Period
- during which time, no stimulus, no matter how large, can elicit an AP
- too many Na+ channels are in the inactivated state to allow attainment of the voltage threshold for an AP
Signaling by APs
- rapid signaling, without decrement over distance
- as signal travels away from point of stimulus, it remains the same amplitude b/c it is regenerated in each patch of membrane that reaches threshold
- more efficient than graded (electrotonic or passive) potentials at propagating signals over long distances
AP Propagation
- as each patch of membrane is depolarized to threshold, an AP is produced which electrotonically propagates to the adjacent patch of membrane
- normally short, & AP current large, thus decrement of the signal is minimal b/w patches of membrane & the new patch is brought to threshold
- typically initiate at 1 point (generally axon initial segment or 1st Node of Ranvier) & propagate along the axon as well as back into the soma & dendritic tree
What would happen if AP stimulus would occur in the middle of a cable?
-propagation would be bidirectional from the point of stimulation
Propagation of AP within the Axon
-usually unidirectional due to Na+ inactivation & the resulting refractory perior
After a given patch has an AP?
- it is normally refractory for a few ms, thus the AP only brings the next patch of membrane (in the direction of movement) to threshold
- APs do not go one way and then turn around and go another
Conduction velocity of an Axon
- rate of advance of AP
- increased by increasing the diameter of the axon (more charge, more surface area, less is lost)
- myelin inc. conduction velocity
Myelin
- lipid that is wrapped around the axon in a glial cell membrane (Schwann cell:PNS, Oligodendrocytes:CNS)
- inc. resistance of of the membrane for ions (since ions can’t pass through lipid & typically axons do not place channels in regions under myelin)
- inc. lipid thickness dec. the ability of the membrane to act as a capacitor (dec. cap. means less charge is stored on the membrane so more charge is available to pass through the axoplasm to the next node of Ranvier
- inc. conduction velocity by restricting the ionic changes leading to APs to the Nodes of Ranvier & faciliting the movement of charge from one node to the next
Nodes of Ranvier
-interruption of myelin sheath by unmyelinated membrane areas
Action Potential Conduction in Unmyelinated Axon
- an AP occurs at a given patch of membrane
- charge electrotonically (passively) propagates to next patch
- if this depolarization reaches threshold, an AP is generated in new patch
- Na+ inactivation causes refractory period which prevents AP from reversing directions
- the conduction velocity of an unmyelinated axon is proportional to axon diameter (large diameter leads to greater velocity)
Action Potential Conduction in Myelinated Axon
- conduction velocity is. inc. by restricting the AP to the Nodes of Ranvier and by facilitating electrotonic movement of charge b/w nodes
- inc. the resistance of the membrane to leakage of ions & dec. the capacitance of the membrane
- AP seems to jump b/w nodes “saltatory conduction”
- Na+ inactivation is more important than K+ activation for repolarization of APs
Spike Initiation Zone
-in neurons its either at the axon initial segment or the 1st Node of Ranvier due to combo of high Na+ channel density & geometric factors
Multiple Sclerosis
- loss of myelin sheath of some axons (demyelination)
- underlying mechanism: inflammation
- initially leads to conduction block b/c the Na+ channels are located too far apart for passive mechanisms to result in depolarization of the next group of channels (old Node)
- distribution can be remodeled, restoring some degree of axonal function
Channelopathies
-mutations in channels which alter function & lead to pathology
Alpha subunit amino acid sequence
- characterized by 4 domains (I-IV), each consisting of 6 transmembrane spanning regions
- 4 domains arranges so as to form the aqueous pore b/w them
- when specific amino acids are mutated, this leads to different types of channelopathy
Point mutations in Sodium Channel Alpha Subunit
- lead to disease
- cause generalized epilepsy with febrile seizures (GEFS) cause slowed inactivation of Na+ channels (the channels remain open too long leading to hyperexcitablity)
Myotonia & Periodic Paralysis
-caused by Na+ channel mutations in skeletal muscle (neurons are not the only excitable cells)
Voltage-Gated Calcium Channel Alpha Subunit
- similar to Na
- 4 domains of 6 transmembrane regions
- several distinct types exist in the brain and other excitable tissues
- mutations can lead to channelopathies
Familial Hemiplegic Migraine
-associated with mutation of P/Q-type Ca2+ channels (CaV2.2: gene name CACNA1A)
Episodic Ataxia Type 2
-due to truncation mutants of Cav2.2 Ca2+ channels`
CSNB
-due to truncated L-type Ca2+ channels in the retina (alters sensitivity of the channels to modulation by calmodulin)
Lambert-Eaton syndrome
- small cell carcinomas produce abs to voltage-gated Ca channels (P/Q type)
- autoimmune activity alters Ca channel function
- clinical manifestations: dysfunction of neuromuscular junction
BFNC - Benign Familial Neonatal Seizures
-most prevalent known cause of BFNE is mutation of KCNQ2 (voltage-gated potassium channel)
Myotonia
- hyperexcitability of muscle
- mutations in voltage-gated Cl- channel
- resting membrane potential of muscle fibers becomes relatively depolarized, making them more excitable
Episodic Ataxia Type 1
-mutations in Kv1.1 type potassium channels in Purkinje cells
