17.VGCC
Voltage-gated Calcium Channels in Neurophysiology
17.1 Spikes and Voltage-gated Ca2+ Channels
Introduction of Voltage-gated Channels: In addition to fast voltage-gated Na+ and K+ channels previously discussed, voltage-gated Ca2+ channels are crucial for neuronal function.
Role of Ca2+ in Neurons: An action potential in many neurons leads to an influx of Ca2+, critical for synaptic transmission.
17.2 The Calyx Synapse
Calyx of Held Synapse: Located in the mammalian auditory system, it allows easy patch-clamping of presynaptic and postsynaptic cells.
Experimental Setup:
Use of Ca2+-sensitive dye (Fura-2) in the presynaptic terminal to measure intracellular Ca2+ concentration.
Action potential generated in the presynaptic terminal (see action potential trace).
Observations: Rapid increase in Ca2+ post-action potential decaying to baseline over ~1 second due to Ca2+ influx through voltage-gated channels.
17.3 Types of Voltage-gated Ca2+ Channels
Overview of Calcium Channels: Five types identified, with initial designations as T, N, and L-types; alpha-1 subunits designated A-H based on gene nomenclature.
Table of Calcium Channels
Channel | Type | g (pS) | Activation (mV) | Inactivation (ms) | Blocker |
|---|---|---|---|---|---|
CaV1.1-4 | L | 25 | >-30 mV | >500 ms | Dihydropyridines |
CaV2.1 | P/Q | 15 | >-30 mV | >500 ms | w-AGA IVA* |
CaV2.2 | N | 15 | >-30 mV | 50-500 ms | w-CTX GVIA** |
CaV2.3 | R | 15 | >-30 mV | ~30 ms | SNX-482 |
CaV3.1-4 | T | 7 | >-70 mV | ~50 ms | Mibefradil |
Voltage-clamp Protocol: Elicit voltage-gated Ca2+ currents; notice inwardly rectifying nature and absence of outward current due to difference in Ca2+ concentration inside vs. outside.
17.3.1 CaV1 Channels (L-type Channels)
Characteristics: High-voltage activated (HVA); slow inactivation primarily through a Ca2+-dependent mechanism.
Inactivation Behavior: Condition-dependent; shows negative-feedback modulation based on intracellular Ca2+ levels. Dihydropyridines block L-type channels.
BAYK Effect: BAY-K8644 increases open probability of L-type channels, enhancing ICaL.
17.3.2 CaV2.1 Channels (P/Q)
Inactivation Profile: Slow to non-inactivating HVA channels, significant in Purkinje neurons and presynaptic terminals.
17.3.3 CaV2.2 Channels (N-type)
Conductance Characteristics: Intermediate single-channel conductance. Inactivate in response to depolarization much like voltage-gated Na+ channels.
N-type Channel Activation: Depolarization-related activation and inactivation patterns; not sensitive to BAYK.
17.3.4 CaV2.3 Channels (R-type)
Residual Current Identification: Active even when L, N, and P/Q channels are blocked; inactivate in a voltage-dependent manner.
17.3.5 CaV3 Channels (T-type)
Activation Properties: Low-voltage activated (LVA), activate at only slightly depolarized voltages.
Inactivation Requirements: Greater depolarization required for inactivation compared to R-type channels.
Pharmacological Challenges: Difficult to isolate due to overlapping effects of blockers; primarily expressed in neuron soma and dendrites.
17.4 Neuron-Specific Expression of Channels
Channel Expression Variability: Ca2+ channels vary by neuron type, influencing the contribution to total Ca2+ current.
17.5 Molecular Structure of CaV Channels
Structural Similarity to Na+ Channels: Share similar architecture; selective for Ca2+ through unique selectivity filter allowing for effective dehydration of Ca2+.