Models of calcium permeation through T-type channels

Ca2+ entry is indispensable part of intracellular Ca2+ signaling, which is vital for most of cellular functions. Low voltage-activated (LVA or T-type) calcium channels belong to the family of voltage-gated calcium channels (VGCCs) which provide Ca2+ entry in response to membrane depolarization. VGCCs are generally characterized by exceptional Ca2+ selectivity combined with high permeation rate, thought to be determined by the presence in their selectivity filter of a versatile Ca2+ binding site formed by four glutamate residues (EEEE motif). The subfamily of LVA channels includes three members, Cav3.1, Cav3.2 and Cav3.3. They all possess two aspartates instead of glutamates (i.e., EEDD motif) in their selectivity filter and are the least Ca2+-selective of all VGCCs. They also have the lowest conductance, weakly discriminate Ca2+, Sr2+ and Ba2+ and demonstrate channel-specific sensitivity to divalent metal blockers, such as Ni2+. The available data suggest that EEDD binding site of LVA channels is more rigid compared to EEEE one, and their selectivity permeation and block are determined by two supplementary low-affinity intrapore Ca2+ binding sites located above and below EEDD locus. In addition, LVA channels have extracellular metal binding site that allosterically regulates channel’s gating, permeation and block depending on trace metals concentration.