Phospholamban interactome in cardiac contractility and survival: A new vision of an old friend

Kobra Haghighi, Philip Bidwell, Evangelia G. Kranias

Research output: Contribution to journalReview articlepeer-review

74 Scopus citations


Depressed sarcoplasmic reticulum (SR) calcium cycling, reflecting impaired SR Ca-transport and Ca-release, is a key and universal characteristic of human and experimental heart failure. These SR processes are regulated by multimeric protein complexes, including protein kinases and phosphatases as well as their anchoring and regulatory subunits that fine-tune Ca-handling in specific SR sub-compartments. SR Ca-transport is mediated by the SR Ca-ATPase (SERCA2a) and its regulatory phosphoprotein, phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA2a and phosphorylation by protein kinase A (PKA) or calcium-calmodulin-dependent protein kinases (CAMKII) relieves these inhibitory effects. Recent studies identified additional regulatory proteins, associated with PLN, that control SR Ca-transport. These include the inhibitor-1 (I-1) of protein phosphatase 1 (PP1), the small heat shock protein 20 (Hsp20) and the HS-1 associated protein X-1 (HAX1). In addition, the intra-luminal histidine-rich calcium binding protein (HRC) has been shown to interact with both SERCA2a and triadin. Notably, there is physical and direct interaction between these protein players, mediating a fine-cross talk between SR Ca-uptake, storage and release. Importantly, regulation of SR Ca-cycling by the PLN/SERCA interactome does not only impact cardiomyocyte contractility, but also survival and remodeling. Indeed, naturally occurring variants in these Ca-cycling genes modulate their activity and interactions with other protein partners, resulting in depressed contractility and accelerated remodeling. These genetic variants may serve as potential prognostic or diagnostic markers in cardiac pathophysiology.

Original languageEnglish (US)
Pages (from-to)160-167
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
StatePublished - Dec 1 2014
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by: NIH grants HL-26057 and HL-64018 to E. G. K. The authors are grateful to Ms. Erica Vanderbilt for her excellent assistance.

Publisher Copyright:
© 2014 Elsevier Ltd.


  • Calcium
  • Contractility
  • Heart failure
  • Human variants
  • Phospholamban
  • Sarcoplasmic reticulum


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