The Distal Carboxy Tail (DCT) of CaV1.4 Modulates More than Ca2+/CaM-Dependent Inactivation (CDI)

Abstract

CaV1.4 L-type Ca2+ channels populate retinal ribbon synapses, and mediate tonic neurotransmitter release. Mutations in the CACNA1F gene encoding CaV1.4 are implicated in congenital stationary night blindness (CSNB2). The K1591X CSNB2 mutation yields a premature stop that deletes the DCT of CaV1.4. Interestingly, the DCT contains a module that competes with Ca2+-free calmodulin (apoCaM) for binding at the IQ-domain of CaV1.4, thereby tuning channel affinity for apoCaM (Nature 463:968). Since only channels ‘charged’ with apoCaM exhibit Ca2+/CaM-mediated inactivation (CDI), wildtype CaV1.4 channels exhibit little or no CDI, while deleting the DCT yields a resurgence of CDI. The latter effect in K1591X channels has suggested that pathogenesis involves abnormally diminished Ca2+ influx with resulting impairment of photoreceptor signaling. Here, however, we observe a dramatic and unrecognized effect of DCT deletion. Single-channel recordings indicate that wild-type CaV1.4 feature diminutive open probability Po (A. Top, exemplar single-channel trace during voltage ramp. Bottom, Po-V relation averaged over multiple patches). By contrast, K1591X channels exhibit strikingly enhanced Po (B). Hence, this form of CSNB2 likely involves an unexpected Ca2+ overload phenomenon, raising the possibility of therapeutics involving CaV1.4 channel blockade.View Large Image | View Hi-Res Image | Download PowerPoint Slide