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Calmodulin (CaM) serves as a pervasive regulatory subunit of Ca V 1, Ca V 2, and Na V 1 channels, exploiting a functionally conserved carboxy-tail element to afford dynamic Ca 2+ -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 Ca 2+ /CaM-regulation of Ca V 1 and Na V 1 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 Ca V 1.3 carboxy-tail confers synthetic switching of CaM regulation by Mona SH3 domain. Overall, our findings identify a general class of auxiliary proteins that modify Ca 2+ /CaM signaling to individual targets allowing spatial and temporal orchestration of feedback, and outline strategies for engineering Ca 2+ /CaM signaling to individual targets.

Allosteric regulators selectively prevent Ca 2+ -feedback of Ca V and Na V channels