TY - JOUR
T1 - Allosteric regulators selectively prevent Ca 2+ -feedback of Ca v and Na v channels
AU - Niu, Jacqueline
AU - Dick, Ivy E.
AU - Yang, Wanjun
AU - Bamgboye, Moradeke A.
AU - Yue, David T.
AU - Tomaselli, Gordon
AU - Inoue, Takanari
AU - Ben-Johny, Manu
N1 - Funding Information:
We thank Deborah DeSilvestre, Rebeca Joca, and Travis Babola for assistance with immunohistochemistry, Hikeki Nakamura for confocal microscope training, Trudeau lab (Ashley Johnson and Sara Coddin) and Colecraft lab (Travis Morgenstern and Scott Kanner) for western blotting expertise. We are grateful for insightful discussions with the Calcium Signals Laboratory and Inoue Synthetic Biology Lab. Finally, we are indebted to the inspiration of Dr. David T Yue, who taught us to pursue science with a passion for the truth. This work was supported by grants from NINDS (DTY, IED, TI), NIMH (DTY, MBJ), NHLBI (GFT) and NSF (JN).
Publisher Copyright:
© Niu et al.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055617349&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055617349&partnerID=8YFLogxK
U2 - 10.7554/eLife.35222
DO - 10.7554/eLife.35222
M3 - Article
C2 - 30198845
AN - SCOPUS:85055617349
SN - 2050-084X
VL - 7
JO - eLife
JF - eLife
M1 - e35222
ER -