Voltage-gated calcium channel · Grey Matter

The voltage-gated calcium channel is the membrane protein that opens when a spike reaches the axon terminal and lets calcium in, and that calcium is the trigger for exocytosis: no calcium entry, no transmitter release.

Voltage-gated calcium channel. The voltage-gated calcium channel is the membrane protein that opens when a spike reaches the axon terminal and lets calcium in, and that calcium is the trigger for exocytosis: no calcium entry, no transmitter release.

Calcium is kept about ten thousand times more concentrated outside a neuron than inside (around 1 to 2 mM against about 100 nM), so when these channels open even a small number of ions raises the local concentration enormously. At the terminal the channels (mostly the P/Q and N types, Cav2.1 and Cav2.2) are anchored within tens of nanometres of docked vesicles, so the calcium that matters is a brief, very local cloud (a nanodomain) rather than a rise across the whole terminal. Fusion follows calcium entry by tens of microseconds at body temperature.

Release depends steeply on calcium. Several calcium ions must bind the sensor synaptotagmin for a vesicle to fuse, so release rises roughly with the fourth power of calcium entry; a small change in channel opening produces a large change in transmitter output.

That steepness makes the channel a control point. GABA-B receptors, endocannabinoid CB1 receptors and other presynaptic receptors reduce release mainly by inhibiting these channels.

Other types do other jobs. L-type channels in cell bodies and dendrites couple activity to gene expression; T-type channels open near rest and support the rhythmic bursting of thalamic neurons, and drugs for absence seizures (ethosuximide) block them.

Calcium is where electricity becomes chemistry.

The spike is a voltage; what the terminal does with it is decided by how much calcium enters and how close it enters to a vesicle.

Questions: Why are calcium channels anchored within nanometres of the vesicles they trigger? Calcium entering through an open channel is buffered and pumped away so fast that its concentration is high only in a tiny cloud around the channel mouth, tens of nanometres across, for well under a millisecond. A vesicle docked inside that cloud sees enough calcium to bind its sensor and fuse almost at once; one docked farther away sees too little, too late. Tethering proteins at the active zone therefore hold the channels next to the docked vesicles, which is what lets fusion follow calcium entry by about 60 microseconds at body temperature. The arrangement also keeps release tied to the spike, since the cloud vanishes as soon as the channels close. Why does a small change in calcium entry change transmitter release so much? A vesicle fuses only when several calcium ions are bound to its sensor, synaptotagmin, so release grows roughly as release∝[Ca2+]4\text{release} \propto [\text{Ca}^{2+}]^{4}release∝[Ca2+]4, a relation first measured by Dodge and Rahamimoff in 1967. With that exponent, calcium entry cut by a fifth leaves 0.84≈0.410.8^{4} \approx 0.410.84≈0.41 of the release. The steepness makes calcium channels a powerful control point: presynaptic receptors for GABA, endocannabinoids or adenosine need only trim calcium entry slightly to silence a synapse. It also makes residual calcium from an earlier spike matter, which underlies facilitation.