Histidine residues in the IS3–IS4 loop are critical for nickel-sensitive inhibition of the Cav2.3 calcium channel

We recently reported that a histidine (H191) in the S3–S4 loop of domain I is critical for nickel inhibition of the Cav3.2 T-type Ca2+ channel. As in Cav3.2, two histidine residues are commonly found in the IS3–IS4 loops of mammalian Cav2.3 Ca2+ channels, which are also blocked by low micromolar concentrations of nickel. We show here by site-directed mutagenesis and electrophysiology that both residues contribute to the nickel sensitivity of Cav2.3, with H183 being more critical than H179. These findings strongly suggest that both H179 and H183 in the IS3–IS4 loop are essential structural determinants required for nickel sensitive inhibition of the Cav2.3.