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Structural and functional implications of the phospholamban hinge domain: impaired SR Ca2+ uptake as a primary cause

Albrecht G Schmidt1, Jing Zhai, Andrew N Carr

  • 1Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA.

Cardiovascular Research
|October 24, 2002
PubMed

Insights

Impaired sarcoplasmic reticulum (SR) calcium sequestration due to a phospholamban mutation causes progressive left ventricular dysfunction and heart failure. The phospholamban hinge domain is critical for this process.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Heart Failure Pathophysiology

Background:

  • The sarcoplasmic reticulum (SR) plays a crucial role in cardiac muscle function by regulating intracellular calcium levels.
  • The exact role of SR dysfunction in the development and progression of heart failure remains debated.
  • Phospholamban (PLB) is a key regulator of the SR Ca2+-ATPase (SERCA), influencing calcium reuptake into the SR.

Purpose of the Study:

  • To investigate the hypothesis that impaired SR calcium sequestration is a primary driver of progressive left ventricular (LV) dysfunction.
  • To determine if the phospholamban hinge domain is critical in the process of LV dysfunction and heart failure.
  • To elucidate the molecular mechanisms linking SR function to heart failure progression.

Main Methods:

  • Generation of a phospholamban hinge domain mutant (PLB/N27A) in a phospholamban-null mouse model.
  • Utilized an integrative approach to assess cardiac phenotype at structural, cellular, organ, and whole-animal levels.
  • Employed Nuclear Magnetic Resonance (NMR) for structural analysis and measured SR Ca2+ ATPase activity via oxalate-supported Ca2+ uptake.

Main Results:

  • NMR revealed altered alpha-helical configuration in the mutant phospholamban hinge domain.
  • Mutant phospholamban caused super-inhibition of SR Ca2+ ATPase, impairing calcium sequestration and leading to diastolic dysfunction.
  • Mutant hearts exhibited a blunted force-frequency relation, LV dilation, and progressed to congestive heart failure with depressed systolic function and increased mortality.

Conclusions:

  • Impaired SR calcium sequestration, particularly involving the phospholamban hinge domain, is a causative factor in left ventricular dysfunction and heart failure.
  • The phospholamban hinge domain is crucial for transmitting regulatory signals to SERCA, impacting cardiac contractility and relaxation.
  • These findings highlight a novel mechanism in heart failure pathogenesis and suggest potential therapeutic targets related to SR calcium handling.
Abstract

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