Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels
Jacqueline Niu,
Ivy E Dick,
Wanjun Yang,
Moradeke A Bamgboye,
David T Yue,
Gordon Tomaselli,
Takanari Inoue,
Manu Ben-Johny
Affiliations
Jacqueline Niu
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States
Ivy E Dick
Department of Physiology, University of Maryland, Baltimore, United States
Wanjun Yang
Department of Cardiology, Johns Hopkins University, Baltimore, United States
Moradeke A Bamgboye
Department of Physiology, University of Maryland, Baltimore, United States
David T Yue
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States
Gordon Tomaselli
Department of Cardiology, Johns Hopkins University, Baltimore, United States
Takanari Inoue
Department of Cell Biology, Johns Hopkins University, Baltimore, United States; Center for Cell Dynamics, Institute for Basic Biomedical Sciences, Johns Hopkins University, Baltimore, United States
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.
