Erbin Enhances Voltage-Dependent Facilitation of Cav1.3 Ca2+ Channels through Relief of an Autoinhibitory Domain in the Cav1.3 α1 Subunit

摘要

Cav1.3 (L-type) voltage-gated Ca²⁺ channels have emerged as key players controlling Ca²⁺ signals at excitatory synapses. Compared with the more widely expressed Cav1.2 L-type channel, relatively little is known about the mechanisms that regulate Cav1.3 channels. Here, we describe a new role for the PSD-95 (postsynaptic density-95)/Discs large/ZO-1 (zona occludens-1) (PDZ) domain-containing protein, erbin, in directly potentiating Cav1.3. Erbin specifically forms a complex with Cav1.3, but not Cav1.2, in transfected cells. The significance of erbin/Cav1.3 interactions is supported by colocalization in somatodendritic domains of cortical neurons in culture and coimmunoprecipitation from rat brain lysates. In electrophysiological recordings, erbin augments facilitation of Cav1.3 currents by a conditioning prepulse, a process known as voltage-dependent facilitation (VDF). This effect requires a direct interaction of the erbin PDZ domain with a PDZ recognition site in the C-terminal domain (CT) of the long variant of the Cav1.3 α1 subunit (α11.3). Compared with Cav1.3, the Cav1.3b splice variant, which lacks a large fraction of the α11.3 CT, shows robust VDF that is not further affected by erbin. When coexpressed as an independent entity with Cav1.3b or Cav1.3 plus erbin, the α₁1.3 CT strongly suppresses VDF, signifying an autoinhibitory function of this part of the channel. These modulatory effects of erbin, but not α₁1.3 CT, depend on the identity of the auxiliary Ca²⁺ channel β subunit. Our findings reveal a novel mechanism by which PDZ interactions and alternative splicing of α₁1.3 may influence activity-dependent regulation of Ca_v1.3 channels at the synapse.