There is significant unmet need for more effective treatments for bipolar disorder. The drug discovery process is becoming prohibitively expensive. Hence, biomarker clues to assist or shortcut this process are now widely sought. Using the publicly available data from the whole genome association study conducted by the Wellcome Trust Case Control Consortium, we sought to identify groups of genetic markers (single nucleotide polymorphisms) in which each marker was independently associated with bipolar disorder, with a less stringent threshold than that set by the original investigators (p⩽1×10−4). We identified a group of markers occurring within the CACNA1C gene (encoding the alpha subunit of the calcium channel Cav1.2). We then ascertained that this locus had been previously associated with the disorder in both a smaller and a whole genome study, and that a number of drugs blocking this channel (including verapamil and diltiazem) had been trialled in the treatment of bipolar disorder. The dihydropyridine-based blockers such as nimodipine that bind specifically to Cav1.2 and are more penetrant to the central nervous system have shown some promising early results; however, further trials are indicated. In addition, migraine is commonly seen in affective disorder, and calcium channel antagonists are successfully used in the treatment of migraine. One such agent, flunarizine, is structurally related to other first-generation derivatives of antihistamines such as antipsychotics. This implies that flunarizine could be useful in the treatment of bipolar disorder, and, furthermore, that other currently licensed drugs should be investigated for antagonism of Cav1.2.

The present study uses cell-attached patch-recording techniques to study the single-channel properties of Ca2+ channels in isolated salamander photoreceptors and investigate their sensitivity to reductions in intracellular Cl−. The results show that photoreceptor Ca2+ channels possess properties similar to L-type Ca2+ channels in other preparations, including (1) enhancement of openings by the dihydropyridine agonist, (−)BayK8644; (2) suppression by a dihydropyridine antagonist, nisoldipine; (3) single-channel conductance of 22 pS with 82 mM Ba2+ as the charge carrier; (4) mean open probability of 0.1; (5) open-time distribution fit with a single exponential (τ0 = 1.1 ms) consistent with a single open state; and (6) closed time distribution fit with two exponentials (τc1 = 0.7 ms, τc2 = 25.4 ms) consistent with at least two closed states. Using a Cl−-sensitive dye to measure intracellular [Cl−], it was found that perfusion with gluconate-containing, low Cl− medium depleted intracellular [Cl−]. It was therefore possible to reduce intracellular [Cl−] by perfusion with a low Cl− solution while maintaining the extracellular channel surface in high Cl− pipette solution. Under these conditions, the single-channel conductance was unchanged, but the mean open probability fell to 0.03. This reduction can account for the 66% reduction in whole-cell Ca2+ currents produced by perfusion with low Cl− solutions. Examination of the open and closed time distributions suggests that the reduction in open probability arises from increases in closed-state dwell times. Changes in intracellular [Cl−] may thus modulate photoreceptor Ca2+ channels.