Download 6 Voltage Regulated Channels

Brain Science Fundamentals
Christopher Fiorillo
BiS 328, Fall 2010
042 350 4326, [email protected]
Part 6: A Neuron’s Membrane Voltage: Beyond the Action
Potential
Reading: Bear, Connors, and Paradiso, Chapter 4.
Assistant: Sora Yun <[email protected]>
Beyond the Action Potential
• The action potential is an effective means of communication
across distance
• Whether an action potential occurs, at each moment in time
depends on the membrane voltage
• Membrane voltage depends on the activity (conductance) of:
– synaptic ion channels
– non-synaptic, voltage-regulated ion channels
• The voltage-gated channels that mediate the action potential
are not very important for determining whether an action
potential occurs
– This is because those channels only become active once membrane
voltage reaches threshold
• There are many types of voltage-regulated ion channels that
are not involved in mediating the action potential, but which
influence whether or not an action potential occurs
Subtreshold membrane voltage determines the pattern of action potentials
• This is from an intracellular recording of a neuron in a living brain.
• Whether a neuron fires an action potential depends on fluctuations in
membrane voltage
– These fluctuations are necessarily subthreshold (below the threshold for an action potential)
• The subthreshold membrane voltage is determined by synaptic inputs and
by voltage-regulated ion channels
Ion Channel Diversity Within and Across Neurons
• There may be about 200 different genes for voltage-regulated
ion channels (in mammals)
• The functional diversity (voltage-dependence and kinetics) is
much greater
– Maybe 1000 or more different types?
– Different combinations of subunits (each encoded by a single gene) can interact to
form a channel
– alternative mRNA splicing
– physical association of additional proteins
– phosphorylation, calcium-binding, modification of lipids, etc
• Different neurons express different types of voltage-regulated
channels
• A single neuron expresses many different types of voltageregulated ion channels
– Maybe 20. No one knows exactly
Voltage-regulated ion channels
• Na+ channels
– depolarization activated
• Ca2+ channels
– depolarization activated
– L-type, T-type, N-type, P-type, Q-type, R-type
– Calcium has many effects inside a neuron, including the activation of K+
channels
• Cl- channels
– depolarization activated; not common
• Cation channels (non-selective; Na+ and K+)
– Hyperpolarizaton activated (“H” current)
• K+ channels
–
–
–
–
Depolarization activated
Most diverse
A-type, M-type, delayed rectifier, inward rectifier, etc.
Multiple types of calcium-activated K+ channels (BK, SK, etc)
Potassium Channel Diversity
Genetic Diversity
• At least 100 genes for K+ channel proteins
• K+ channel diversity is much greater than Na+, Ca2+, or
Cl- channel diversity
• Functional diversity is much greater than genetic diversity
– Post-translational and post-transcriptional modification, subunit
combinations, regulation (e.g. phosphorylation)
• K+ channel types with different kinetics carry information from
different periods of the past
Diversity of K+ Channel Kinetics
ventricular
myocytes
5 s voltage
steps
200 ms
Kv4.3
2000 ms
The AfterHyperpolarization
in Hippocampal
Pyramidal
Neurons
•
Three components to the AHP, mediated by 4 K+ channel types
– Fast (lasts about 5 ms)
• BK-type K+ channels, activated synergistically by calcium and voltage
– Medium (lasts about 100 ms)
• M-type K+ channel, voltage-activated
• Calcium-activated K+ channel
– Slow (lasts about 2 seconds, but requires multiple action potentials to become large)
• Calcium-activated K+ channel (Kv7)
H-current (HCN channels)
• HCN channels are hyperpolarization activated, non-selective cation
channels that underlie the “H-current”
• The image at left shows slow activation of H-current in response to
hyperpolarizing voltage steps
• The image at right shows the membrane voltage in response to a
square-wave pulse of hyperpolarizing or depolarizing current
Why is there so much diversity of voltageregulated ion channels?
• Voltage-regulated ion channels exhibit great diversity in their kinetic properties
• Different types of channels with different kinetics carry information from different
periods of the past
• By choosing to express one type of channel rather than another, a neuron is choosing to
receive information from one period of the past rather than another
• Different synapses represent different regions of space
• Thus, the variety of distinct types of voltage-regulated ion channels is analogous to the
the variety of discrete synapses
• The neuron can choose those that are most appropriate, given its unique environment
200
Kv4.3
2000
Functional Classification of Ion Channels
• Excitatory (Na+, Ca2+, mixed cation) versus Inhibitory (K+, Cl-)
• Stabilizing versus Destabilizing
• Stabilizing channels function to maintain membrane voltage at an
intermediate level. Thus they act to maintain homeostasis.
– This can occur through negative feedback
– Examples: Depolarization-activated K+ channels, hyperpolarization
activated cation channels
• Destabilizing channels function to shift membrane voltage away
from an intermediate level.
– This can occur through positive feedback
– Examples: Depolarization -activated Na+ or Ca2+ channels,
hyperpolarization-activated K+ channels
• Whether a channel is stabilizing or destabilizing depends on the statistical patterns of the
voltage in relation to the specific properties of the channel (not just on whether it exhibits
positive or negative feedback). But in general, negative feedback promotes homeostasis
(stability) and positive feedback does not.
Maintaining Homeostasis
• Voltage-regulated ion channels act to maintain homeostasis
• Homeostasis means keeping the membrane voltage at an
intermediate level
– Slightly below the threshold for an action potential
• Maintaining homeostasis is difficult because the synaptic
excitation varies in intensity over a large range, and it can
have complex temporal patterns
• The mechanisms that act to maintain homeostasis must have
information about the synaptic excitation
– If they have information about synaptic excitation, that means that they
predict synaptic excitation
• If a neuron acts to maintain its homeostasis, then its output can be
understood as a prediction error
– In an information processing system, homeostasis and prediction error are
essentially the same thing
Homeostasis maintained by Potassium Channels
Glutamate-gated Cation Channels
Voltage-gated Potassium Channels
•Both glutamate-gated channels and voltage-gated channels contain information about
glutamate concentration.
•Thus, the K+ channels estimate or predict glutamate concentration
•At any given moment, the information of the K+ channels about glutamate is “older” than that of
the glutamate-gated channels
•The neuron’s output depends on the difference between the K+ conductance (contributing prior
information) and the glutamate-gated conductance (contributing current information)
•The neuron’s output can be thought of as a prediction error
Summary of a Neuron’s Physiology
• Inputs to a neuron:
– Non-synaptic, voltage-regulated ion channels carry
information from the past
• The conductance of these channels at each brief moment
depends on the history of a neuron’s voltage
• Different types of channels represent different periods of the
past, depending on their kinetics
– Synaptic inputs represent points in space
• The conductance of these channels depends on the release of
neurotransmitter at a specific synapse
• A neuron’s output depends on integration of the
conductances of all of its ion channels
– At any moment in time, a neuron receives both excitation
and inhibition, and these arise from both synaptic and nonsynaptic processes.