Abstract
(CDI) and facilitation (CDF), respectively, which contribute to short-term synaptic plasticity. Both CDI and CDF are mediated by calmodulin (CaM) binding to sites in the C-terminal domain (CT) of the Cav2.1 α1 subunit, including a consensus CaM-binding IQ-domain. Cav2.2 (N-type) channels display CDI but not CDF but the underlying mechanism that blocks CDF in Cav2.2 is unknown. Here, we tested the hypothesis that Cav2.2 does not undergo CDF since it lacks essential molecular determinants for CDF that are present in Cav2.1. We find that alternative splicing of exons in the proximal and distal CT, which regulates CDF of Cav2.1, has no effect on CDF of Cav2.2. However, replacement of the entire CT of Cav2.2 with that of Cav2.1 produces robust CDF of the chimeric channel. Further analyses reveal that transfer of the Cav2.1 EF-hand, Pre-IQ- IQ domains, and a downstream CaM-binding domain (CBD) are sufficient to support CDF in chimeric Cav2.2 channels. Our results highlight the importance of the CT in distinguishing Ca2+ feedback regulation of Cav2.2 and Cav2.1, and underscore how molecular distinctions may underlie the unique contributions of these channels in regulating neurotransmitter release.
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