Discovery of phospholamban. A personal history.
Early efforts to identify mechanisms by which sympathetic stimulation increases myocardial contractility led to studies of effects of beta-adrenergic agonists and cyclic AMP on the cardiac contractile proteins and sarcoplasmic reticulum (SR); initial positive reports, however, could not be confirmed. The discovery that cyclic AMP-dependent protein kinases (PK-A) mediated intracellular actions of cyclic AMP led at least four groups to test the hypothesis that phosphorylation of the cardiac SR played a role in the actions of beta-adrenergic agonists. Three of them (Wollenberger, Wray et al., and LaRaia & Morkin) demonstrated that cardiac SR was a substrate for PK-A phosphorylation; however, the lability of the Ca2+ pump in these membranes made it difficult to demonstrate a functional significance of this finding. Our group, which had extensive experience in measuring SR Ca2+ transport, began by examining the ability of PK-A to activate the SR Ca2+ pump "poised" at half-saturating Ca2+ concentrations. Our initial positive result led to the discovery that a 22,000-dalton protein, named phospholamban by Phyllis B. Katz, mediated effects on Ca2+ transport by the SR that could explain both the inotropic and lusitropic effects of sympathetic stimulation.
Katz
A M
AM
Department of Medicine, University of Connecticut Health Center, Farmington 06030-2249, USA. akatz@nsol.uchc.edu
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D003285:Contractile Proteins / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004734:Energy Metabolism; D006321:Heart / Q000502:physiology*; D006801:Humans; D009200:Myocardial Contraction / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D000099211:Phospholamban
D000318:Adrenergic beta-Agonists; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D003285:Contractile Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D000099211:Phospholamban