lec 5 - neurophysiology Flashcards
Neurotransmission is regulated by channels located on distinct regions of the neuron:
Chemically-/Ligand-gated channels
Voltage-gated Na+ and K+ channels
Voltage-gated Ca2+ channels
Leakage Na+ and K+ channels
Chemically-/Ligand-gated channels:
on dendrites and cell bodies to respond to neurotransmitter binding
also called ligand-gated ion channels
open or close in response to the binding of a ligand (i.e., a neurotransmitter) to a receptor.
Ligand-gated ion channels are preferentially distributed on the dendrites and cell body of the neuron
Voltage-gated Na+ and K+ channels:
along axons to regulate action potential propagation
voltage (i.e., electrical) dependent, meaning they are opened at some membrane potentials and are closed at other membrane potentials.
These channels are generally ion selective
Voltage-gated sodium and potassium channels =
major contributors to neuronal action potentials
highest concentration at the initial segment of the axon and at the nodes of Ranvier in myelinated axons
channels are absent in the dendrites and cell bodies
Voltage-gated calcium channels =
important for neurotransmitter release
primarily found at axon/synaptic terminals as calcium is essential for releasing neurotransmitters into the synaptic cleft
Leakage Na+ and K+ channels:
along entire neuron to contribute to resting membrane potential
Leakage channels are always open
ungated but are selective for ions
Leakage channels for potassium or sodium are present along the entire neuron membrane
Leakage channels use passive transport (do not require energy)
____ channels establish the neuronal resting membrane potential
Potassium leakage
Chemically-/Ligand-gated vs. voltage-gated channels
Chemically-/Ligand-gated channels
> Closed under normal conditions (resting membrane potential)
> Selective binding of neurotransmitters opens channel
Voltage-gated channels
> Closed under normal conditions
> Change in membrane voltage opens channel
Chemically-/Ligand-gated channels
Distinct ion selectivity and open time:
ACh and NMDA receptors: Na+ influx
> excitatory NT’s cause depolarization
GABA receptors: Cl- influx and K+ efflux
> inhibitory NT’s cause hyperpolarization
Voltage-gated channels
Distinct ion selectivity and open time:
Voltage-gated Na+ channel: Na+ influx
Voltage-gated K+ channel: K+ efflux
Voltage-gated Ca2+ channel: Ca2+ influx
Na+/K+ pump (Na+/K+ ATPase)
Pumps 3 Na+ out of neuron and 2 K+ into neuron
Uses ATP to pump Na+ and K+ against their electrochemical gradients
Restores resting membrane potential after an action potential
Ca2+ pump (Ca2+ ATPase)
Pumps Ca2+ out of neuron
Uses ATP to pump Ca2+ against its electrochemical gradient
Restores Ca2+ concentration after Ca2+ influx for neurotransmitter release
In addition to ligand-gated, voltage-gated, and leakage channels, the neuronal membrane also contains pumps that move ions against their chemical gradient and, thus, require energy (e.g., ATP)
sodium enters the neuron and potassium exits the neuron during an action potential
ions must get back to where they started = movement is moving against their concentration gradient
must be pumped back using an energy dependent process
sodium and potassium will be pumped using the sodium-potassium ATPase/pump, which uses ATP to pump three sodium ions out of the cell and two potassium ions into the cell
In addition to restoring the sodium and potassium concentrations (via the sodium-potassium pump), calcium concentration must be restored after the calcium influx at the synaptic/axon terminal to promote neurotransmitter release
calcium-ATPase/pump pumps calcium ions out of the neuron to restore the intracellular calcium concentration
Membrane potential (V):
voltage inside cell relative to outside cell
Resting membrane potential (RMP):
membrane potential of a resting cell
Depolarization:
membrane potential becomes more positive
Hyperpolarization:
membrane potential becomes more negative
Membrane resistance (R):
resistance the membrane has to ion flow
Current (I):
flow of electrical charge
Neurons carry electrical current in the form of ions travelling across the membrane
Neurons carry electrical current in the form of ions with positive ___ or negative___ charges
(cations)
(anions)
Ions are located in ____ as well as the ____. The ions are separated by a ____. This separation of charge creates a ____ across the membrane. The difference in charge is referred to as the ____.
neuronal cytoplasm
interstitial fluid
plasma membrane
”potential” difference
membrane potential (V)
Even in the absence of any synaptic input there is a potential difference between the inside and outside of the neuron. The membrane potential in an inactive/resting neuron without any synaptic stimulation is called the ____
resting membrane potential
When synaptic input occurs, the inside of the neuron can become more positive ___ or more negative ___ relative to the resting state.
(depolarized)
(hyperpolarized)
The membrane also acts as a capacitor to separate charge and resist the flow of ions across the membrane. The ___ is defined as the amount of resistance to ion flow. The number, type, and permeability of channels and pumps on the plasma membrane changes the membrane resistance. ___ increases membrane resistance, as it further separates the charge of the cytoplasm Internal neuronal environment) and the charge of the interstitial fluid (external environment). Thus, myelin makes it ___ for ions to flow through the plasma membrane.
membrane resistance
Myelin
harder
Neuronal RMP
Most neurons have a resting membrane potential (RMP) of -70mV
More K+ and protein anions inside the neuron than outside
More Na+, Ca2+, and Cl- outside the neuron than inside
K+ leakage channels are located throughout the neuronal membrane and are always open, allowing K+ to flow down its chemical gradient and leave the neuron
Neurons have a differential distribution of ions across the plasma membrane:
approximately 30 times more potassium inside a neuron than outside a neuron
about 10 times more sodium outside a neuron than inside a neuron
more chloride and calcium ions outside the neuron than inside the neuron
There are more ___ proteins inside the neuron compared to outside the neuron and these proteins are ___ to the membrane.
negative
impermeable
Neuronal RMP Mechanisms
K+ leakage channels establish the RMP by allowing K+ diffusion down its chemical gradient (efflux)
> Neuronal membranes have fewer Na+ leakage channels
> RMP is closer to EK than ENa
Na +/K+ ATPase maintains and restores the RMP by pumping 2 K+ in and 3 Na+ out against their electrochemical gradient
Changes in RMP can produce 2 types of signals:
graded potentials and action potentials
Graded Potentials
passive currents
The degree of the potential is based on the magnitude of the stimulus
The intensity of the signal decays with distance
Graded potentials include EPSPs and IPSPs
Synaptic inputs on the dendrite or cell body release neurotransmitters (NTs) that bind to ligand-gated channels on the post-synaptic membrane:
> channel pore opens
ions enter or leave the neuron
creates a local excitatory post-synaptic potential (EPSP) = causes depolarization
or
creates a local inhibitory post-synaptic potential (IPSP) = causes hyperpolarization
The degree of the potential is based on the magnitude of the stimulus (e.g., dropping a small pebble in a pond vs. dropping a large rock in a pond)
we refer to the potential created by synaptic inputs as graded potentials because
they can be of different sizes and can be summed to reach a critical threshold value
The locally injected current spreads through the neuron’s cytoplasm (much like the waves created by dropping a pebble or rock into a pond). The current decays with distance from the site of current injection (i.e., synapse location). This decay is due to two currents:
Ohmic current: ions exiting through leakage channels at the site of stimulation
Capacitive current: ions moving through the cytoplasm before exiting at other leakage channels
This differs from action potentials, in which current spreads over long distances using an all-or-none mechanism
Excitatory Post-Synaptic Potential (EPSP)
Excitatory NT binds to its receptor and opens a ligand-gated channel
Na+ moves into the cell, causing depolarization
EPSPs bring neuronal membrane potential closer to threshold
EPSPs mostly occur on dendritic spines
Inhibitory Post-Synaptic Potential (IPSP)
Inhibitory NT binds to its receptor and opens a ligand-gated channel
> K+ channel allowing K+ efflux
> Cl- channel allowing Cl- influx
K+ efflux or Cl- influx causes hyperpolarization
IPSPs take neuronal membrane potential further away from threshold
IPSPs mostly occur on dendritic shafts and neuronal cell bodies
Threshold Potential
Action potentials are regulated by spatiotemporal changes in membrane potential
Reaching the threshold potential for opening of voltage-gated Na+ channels is key for action potential generation
Summation of Graded Potentials
Graded potentials must be summed to reach threshold
Neurons have thousands of synapses on their dendrites and cell bodies
Some of these synapses are excitatory and some are inhibitory
The sum of all these synapses determines if an action potential will fire or not
Action Potentials
mediated by voltage-gated Na+ channels and voltage-gated K+ channels
In contrast to graded potentials, which are mediated by leakage channels (mostly potassium leakage channels), action potentials are mediated by voltage-gated channels, including both sodium voltage-gated channels and potassium voltage-gated channels
Once all the graded potentials created by synaptic input and local depolarization reach threshold, the neuron will depolarize due to influx of sodium ions through voltage-gated sodium channels
Once voltage-gated sodium channels are inactivated (inactivation gate blocks channel pore), no more sodium can enter the neuron
Voltage-gated potassium channels open to allow potassium efflux, resulting in ___ to the resting membrane potential. However, potassium channels stay open longer, resulting in more potassium entering than necessary, causing ___ below the resting membrane potential.
repolarization
hyperpolarization
Action potentials are all-or-none
Once threshold is reached, an action potential is initiated
If threshold is not reached, no action potential is initiated
Action potentials do not get bigger with greater depolarization
Unlike graded potentials, where the current can be summed, once threshold is reached for an action potential, the response is all or none
making the stimulus greater or larger does not cause a larger (greater amplitude) action potential.
Voltage-Gated Na+ Channel
Selective for Na+
Two gates: activation and inactivation gate
Three states: closed, opened, and inactivated
closed at resting state - no Na+ enters the cell through them
opened by depolariazation - Na+ can center the cell
inactivated - channels automatically blocked by inactivation gates soon after they open
Voltage-gated sodium channels have gating mechanisms that block the channel pore
the two gates creates three potential states for this channel:
Open and allowing sodium influx = activation gate and inactivation gate are open
Inactive = inactivation gate blocking the pore
> no matter how strong the stimulus is, the pore cannot be opened
> occurs during the absolute refractory period
> No action potential can be initiated during this time
Closed but ready to be opened to allow sodium influx = inactivation gate is open, but the activation gate is closed
> occurs during the relative refractory period
> action potential can occur here, but it requires a larger stimulus
Voltage-Gated K+ Channel
Selective for K+
One gate: voltage sensitive gate
Two states: closed and opened
Opening is delayed compared to opening of voltage-gated Na+ channel
Voltage-gated potassium channels lack an inactivation gate; thus, they have a single gate and two possible states
Closed: no ion flow, but ready to be opened
> Gate is closed
> closed at resting state so no K+ exits the cell
Open: allow potassium efflux
> Gate is open
> opening for voltage-gated potassium channels is delayed relative to the opening of the voltage-gated sodium channels
> opened by depolarization, after a delay, K+ exits the cell
Action Potentials
5 Steps
1) a local potential depolarizes the axolemma of the axon hillock to threshold
2) voltage-gated Na+ channels activate, Na+ enter, axon section depolarizes
3) Na+ channels inactivate and voltage-gated K+ channels activate = Na+ stops entering and K+ exits the axon = repolarization begins
4) Na+ channels return to the resting state = repolarization continues
5) axolemma may hyperpolarize before K+ channels return to resting state = after, axolemma returns to resting membrane potential
Absolute refractory period:
no action potential can be initiated
Voltage-gated Na+ channels are inactivated
Lasts about 1-2msec
Keeps unidirectional flow of action potentials
Relative refractory period:
an action potential can be generated, but it requires a stronger stimulus
Voltage-gated Na+ channels are closed
Lasts about 4msec
Action Potential Frequency
determined by stimulus intensity
Stronger stimulus = increases neuro-transmitter release = increases action potential frequency
limited by absolute refractory period
Conduction velocity is dependent on two factors:
Axon diameter: larger diameter = decreased resistance to current flow = faster signal velocity
Axon myelination: myelin increases membrane resistance, which increase signal velocity
Axon myelination:
More important factor impacting conduction velocity
This leakage property leads to the decay of the action potential over a distance
myelin covers the leakage channels, therefore, current flows down the axon rather than out of the neuron
Saltatory conduction:
action potential only regenerates at nodes of Ranvier, where voltage-gated Na+ channels are exposed, resulting in faster velocity
neurons have leakage channels throughout their entirety, and that there are more ___ leakage channels than ___ leakage channels; thus, more potassium ___ than sodium ___. Thus, the cell becomes more negative (___) and may not have enough current to activate the next voltage-gated sodium channels further down the axon.
potassium
sodium
leaks out
leaks in
hyperpolarized
Demyelinating diseases affecting the CNS
Multiple sclerosis (MS): chronic progressive inflammatory disease, causing CNS demyelination
Demyelinating diseases affecting the PNS
Guillain-Barré syndrome: acute immune-mediated disease caused by infections (e.g., Epstein-Barr or influenza virus) that results in PNS demyelination
Charcot Marie Tooth (CMT): genetic disease that causes peripheral demyelination
