1. A Selectivity Filter Gate Controls Voltage-Gated Calcium Channel Calcium-Dependent Inactivation
- Author
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Abderemane-Ali, Fayal, Findeisen, Felix, Rossen, Nathan D, and Minor, Daniel L
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,1.1 Normal biological development and functioning ,Animals ,Aspartic Acid ,Calcium ,Calcium Channels ,L-Type ,Calcium Channels ,N-Type ,HEK293 Cells ,Humans ,Ion Channel Gating ,Mutation ,Oocytes ,Patch-Clamp Techniques ,Xenopus laevis ,Ca(V)1.2 ,Ca(V)1.3 ,Ca(V)2.1 ,calcium-dependent inactivation ,electrophysiology ,selectivity filter ,voltage-gated calcium channel ,voltage-gated ion channel ,Neurosciences ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
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. more...
- Published
- 2019