Structural and Functional Diversity of Voltage-Activated Calcium Channels

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Abstract
Action potentials and neurotransmitters are the vehicle of information transfer in the nervous system. The diversity of this information is in part encoded by the quantitative contribution and properties of the ion channels underlying both the action potential and the events that follow. As such, voltage-dependent Ca2+ channels represent one class of these ion channels that have both a remarkable ubiquity and importance in a variety of cell types. At rest, there is normally a 10,000-fold concentration difference between intracellular and extracellular Ca2+ concentrations. Intracellular Ca2+ concentrations are normally in the 10–100 nM range, whereas outside cells, the Ca2+ concentration is about 1–2 mM. Elevations of the intracellular Ca2+ concentrations can occur not only as a result of the increase in activity of voltage-sensitive Ca2+ channels, but also in response to the activation of ligand-gated ion channels (NMDA-sensitive glutamatergic receptors or nicotinic ACh receptors) or through the release of Ca2+ from intracellular pools (IP3-and/or ryanodine-sensitive). During increases in voltage-dependent Ca2+ channel activity, the cytosolic Ca2+ can reach concentrations up to 100 μM immediately beneath the plasma membrane. This rise in intracellular Ca2+ is generally not homogeneous but instead seems to be highly organized in space and time. The buffering activity of numerous cellular proteins, which bind Ca2+ tightly and rapidly, limits the spatial diffusion of transient cytosolic Ca2+ increases and keeps the overall Ca2+ concentration to a low free level. Several other mechanisms also ensure an effective buffering of free cytoplasmic Ca2+ in the cell. In the plasma membrane, the Ca2+-ATPase and the electrogenic Na+/Ca2+ exchanger can effectively extrude Ca2+ from the cell. Several intracellular Ca2+ stores (endoplasmic reticulum and mitochondria) will also accumulate Ca2+ by activating a Ca2+-ATPase or a Ca2+/2H+ exchanger.