Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels

Author:

Niu Jacqueline1,Dick Ivy E2,Yang Wanjun3,Bamgboye Moradeke A2,Yue David T1,Tomaselli Gordon3,Inoue Takanari45,Ben-Johny Manu6ORCID

Affiliation:

1. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States

2. Department of Physiology, University of Maryland, Baltimore, United States

3. Department of Cardiology, Johns Hopkins University, Baltimore, United States

4. Department of Cell Biology, Johns Hopkins University, Baltimore, United States

5. Center for Cell Dynamics, Institute for Basic Biomedical Sciences, Johns Hopkins University, Baltimore, United States

6. Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, United States

Abstract

Calmodulin (CaM) serves as a pervasive regulatory subunit of CaV1, CaV2, and NaV1 channels, exploiting a functionally conserved carboxy-tail element to afford dynamic Ca2+-feedback of cellular excitability in neurons and cardiomyocytes. Yet this modularity counters functional adaptability, as global changes in ambient CaM indiscriminately alter its targets. Here, we demonstrate that two structurally unrelated proteins, SH3 and cysteine-rich domain (stac) and fibroblast growth factor homologous factors (fhf) selectively diminish Ca2+/CaM-regulation of CaV1 and NaV1 families, respectively. The two proteins operate on allosteric sites within upstream portions of respective channel carboxy-tails, distinct from the CaM-binding interface. Generalizing this mechanism, insertion of a short RxxK binding motif into CaV1.3 carboxy-tail confers synthetic switching of CaM regulation by Mona SH3 domain. Overall, our findings identify a general class of auxiliary proteins that modify Ca2+/CaM signaling to individual targets allowing spatial and temporal orchestration of feedback, and outline strategies for engineering Ca2+/CaM signaling to individual targets.

Funder

National Science Foundation

National Institute of Neurological Disorders and Stroke

National Institute of Mental Health

National Heart, Lung, and Blood Institute

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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