Abstract
In the retina, Ca(2+) influx through Ca(v)1.4 Ca(2+) channels triggers neurotransmitter release from rod and cone photoreceptors. Changes in extracellular pH modify channel opening, enabling a feedback regulation of photoreceptor output that contributes to the encoding of color and contrast. However, the mechanisms underlying pH-dependent modulation of Ca(v)1.4 are poorly understood. Here, we investigated the role of the C-terminal domain (CTD) of Ca(v)1.4 in pH-dependent modulation of Ba(2+) currents (I(Ba)) in HEK293T cells transfected with the full length Ca(V)1.4 (FL) or variants lacking portions of the CTD due to alternative splicing (Δe47) or a disease-causing mutation (K1591X). While extracellular alkalinization caused an increase in I(Ba) for each variant, the magnitude of this increase was significantly diminished (~40-50%) for both CTD variants; K1591X was unique in showing no pH-dependent increase in maximal conductance. Moreover, the auxiliary α(2)δ-4 subunit augmented the pH sensitivity of I(Ba), as compared to α(2)δ-1 or no α(2)δ, for FL and K1591X but not Δe47. We conclude that the CTD and α(2)δ-4 are critical determinants of pH-dependent modulation of Ca(v)1.4 and may influence the processing of visual information in normal and diseased states of the retina.