A luminal kinase regulates sarcoplasmic reticulum calcium cycling and heart disease

Abstract

The mechanisms and machinery regulating calcium cycling through the sarcoplasmic reticulum (SR) remain incompletely understood, and further insight is critical for discerning normal and diseased heart function. An overlooked component is luminal SR protein phosphorylation. Our lab recently identified a protein kinase in the secretory pathway lumen, Fam20C, which phosphorylates Ser within Ser‐x‐Glu/pSer motifs. Fam20C is responsible for generating the majority of the secretory phosphoproteome. However, Fam20C's role in cardiac function is currently undefined.Here we show that cardiac histidine‐rich calcium binding‐protein (HRC) is a Fam20C substrate. Importantly, a common HRC Ser96Ala genetic mutation causes deadly arrhythmias in patients. The functional significance of this mutation is to block Fam20C phosphorylation at Ser96. Furthermore, several other calcium regulating luminal SR proteins are Fam20C substrates, suggesting that Fam20C plays a broad and impactful role in SR function.We developed a cardiac‐specific Fam20C mouse knockout (KO) model. Using transverse aortic constriction (TAC), we show that Fam20C protects against heart failure. Fam20C KO mice show altered levels of SR calcium handling proteins during TAC, suggesting that calcium cycling through the SR is perturbed. Furthermore, we demonstrate that contractility is altered in Fam20C KO mice.In summary, we introduce Fam20C as a novel yet critical regulator of SR calcium cycling and cardiac biology. The phosphorylation of SR luminal cardiac proteins by Fam20C plays an important role in SR calcium dynamics and heart disease.Support or Funding InformationNHLBI RUTH L. KIRSCHSTEIN NRSA F32 HL136122‐01This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.