A Selectivity Filter Gate Controls Voltage-Gated Calcium Channel Calcium-Dependent Inactivation

• Published in: Neuron (Cambridge, Mass.) Vol. 101; no. 6; pp. 1134 - 1149.e3
• Main Authors: Abderemane-Ali, Fayal, Findeisen, Felix, Rossen, Nathan D., Minor, Daniel L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.03.2019; Elsevier Limited
• Subjects: Animals; Aspartic Acid; Binding sites; Calcium - metabolism; Calcium channels; Calcium channels (voltage-gated); Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Calcium Channels, N-Type - genetics; Calcium Channels, N-Type - metabolism; calcium-dependent inactivation; CaV1.2; CaV1.3; CaV2.1; Channel gating; electrophysiology; Experiments; Gene expression; HEK293 Cells; Humans; Ion Channel Gating - genetics; Mutation; Oocytes - metabolism; Patch-Clamp Techniques; selectivity filter; Sensors; Statistical analysis; voltage-gated calcium channel; voltage-gated ion channel; Xenopus laevis; voltage-gated calcium channel; selectivity filter; electrophysiology; voltage-gated ion channel; CaV1.3; calcium-dependent inactivation; CaV1.2; CaV2.1; Ca(V)1.2; Ca(V)2.1; Ca(V)1.3
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2019.01.011

Calcium-dependent inactivation (CDI) is a fundamental autoregulatory mechanism in CaV1 and CaV2 voltage-gated calcium channels. Although CDI initiates with the cytoplasmic calcium sensor, how this event causes CDI has been elusive. Here, we show that a conserved selectivity filter (SF) domain II (DII) aspartate is essential for CDI. Mutation of this residue essentially eliminates CDI and leaves key channel biophysical characteristics untouched. DII mutants regain CDI by placing an aspartate at the analogous SF site in DIII or DIV, but not DI, indicating that CaV SF asymmetry is key to CDI. Together, our data establish that the CaV SF is the CDI endpoint. Discovery of this SF CDI gate recasts the CaV inactivation paradigm, placing it squarely in the framework of voltage-gated ion channel (VGIC) superfamily members in which SF-based gating is important. This commonality suggests that SF inactivation is an ancient process arising from the shared VGIC pore architecture. [Display omitted] •CaV selectivity filter forms the calcium-dependent inactivation (CDI) endpoint•Conserved CaV domain II selectivity filter (+1) aspartate plays an active role in CDI•CaV selectivity filter asymmetry is important for CDI•CaVs gating relies on an SF-based gating framework shared among the VGIC superfamily Calcium-dependent inactivation (CDI) is essential for voltage-gated calcium channel (CaV) autoregulation. Abderemane-Ali et al. demonstrate that the CaV selectivity filter (SF) forms the CDI gate, suggesting an SF-based inactivation paradigm shared with other voltage-gated ion channel (VGIC) superfamily members.