Phospholamban: a major determinant of the cardiac force-frequency relationship.
The cardiac force-frequency relationship has been known for over a century, yet its mechanisms have eluded thorough understanding. We investigated the hypothesis that phospholamban, a potent regulator of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), determines the cardiac force-frequency relationship. Isolated left ventricular papillary muscles from wild-type (WT) and phospholamban knockout (KO) mice were stimulated at 2 to 6 Hz. The force-frequency relationship was positive in WT but negative in KO muscles, i.e., it was inverted by ablation of phospholamban (P < 0.01, n = 6 mice). From 2 to 6 Hz, relaxation accelerated considerably (by 10 ms) in WT muscles but only minimally (by 2 ms) in KO muscles (WT vs. KO: P < 0. 0001, n = 6). To show that the lack of frequency potentiation in KO muscles was not explained by the almost maximal basal contractility, twitch duration was prolonged in six KO muscles with the SERCA inhibitor cyclopiazonic acid to WT values. Relaxation still failed to accelerate with increased frequency. In conclusion, our results clearly identify phospholamban as a major determinant of the cardiac force-frequency relationship.
Bluhm
W F
WF
Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Kranias
E G
EG
Dillmann
W H
WH
Meyer
M
M
D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D005576:Colforsin / Q000494:pharmacology; D004558:Electric Stimulation; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D010210:Papillary Muscles / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D013997:Time Factors; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D005576:Colforsin; D004791:Enzyme Inhibitors; D007211:Indoles; D000099211:Phospholamban; C000543:cyclopiazonic acid