Molecular elements of ion permeation and selectivity within calcium channels

Voltage-dependent calcium channels are located in the plasma membrane and form a highly selective conduit by which Ca2+ ions enter all excitable cells and some nonexcitable cells. Extensive characterization studies have revealed the existence of one low (T) and five high-voltage-activated calcium channel types (L, N, P, Q, and R). The high voltage-activated calcium channels have been found to exist as heteromultimers, consisting of an alpha1, beta, alpha2/delta, and gamma subunit. Molecular cloning has revealed the existence of 10 channel transcripts, and expression of these cloned calcium channel genes has shown that basic voltage-activated calcium channel function is strictly carried by the corresponding alpha1 subunits. In turn, the auxiliary subunits serve to modulate calcium channel function by altering the voltage dependence of channel gating, kinetics, and current amplitude, thereby creating a likelihood for calcium channels with multiple properties. Although for calcium channels to be effective, Ca2+ ions must enter selectively through the pore of the alpha1-subunit, bypassing competition with other extracellular ions. The structural determinants of this highly selective Ca2+ filter reside within the four glutamic acid residues located at homologous positions within each of the four pore-forming segments. Together, these residues form a single or multiple Ca2+ affinity site(s) that entrap calcium ions, which are then electrostatically repulsed through the intracellular opening of the pore. This mechanism of high-selectivity calcium filtration, the spatial arrangement of pore glutamic acid residues, and the coordination chemistry of calcium binding are discussed in this review.