Role of the C-terminal domain in modifying pH-dependent regulation of Cav1.4 Ca2+ channels.

In the retina, Ca²⁺ influx through Ca_v1.4 Ca²⁺ 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_v1.4 are poorly understood. Here, we investigated the role of the C-terminal domain (CTD) of Ca_v1.4 in pH-dependent modulation of Ba²⁺ currents (I_Ba) in HEK293T cells transfected with the full length Ca_V1.4 (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 α₂δ-4 subunit augmented the pH sensitivity of I_Ba, as compared to α₂δ-1 or no α₂δ, for FL and K1591X but not Δe47. We conclude that the CTD and α₂δ-4 are critical determinants of pH-dependent modulation of Ca_v1.4 and may influence the processing of visual information in normal and diseased states of the retina.