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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Expression of active p21-activated kinase-1 induces Ca²⁺ flux modification with altered regulatory protein phosphorylation in cardiac myocytes

¹Department of Physiology and Biophysics and ²Section of Cardiology, Department of Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois

Submitted 10 January 2008 ; accepted in final form 10 October 2008

p21-Activated kinase-1 (Pak1) is a serine-threonine kinase that associates with and activates protein phosphatase 2A in adult ventricular myocytes and, thereby, induces increased Ca²⁺ sensitivity of skinned-fiber tension development mediated by dephosphorylation of myofilament proteins (Ke Y, Wang L, Pyle WG, de Tombe PP, Solaro RJ. Circ Res 94: 194–200, 2004). We test the hypothesis that activation of Pak1 also moderates cardiac contractility through regulation of intracellular Ca²⁺ fluxes. We found no difference in field-stimulated intracellular Ca²⁺ concentration ([Ca²⁺]_i) transient amplitude and extent of cell shortening between myocytes expressing constitutively active Pak1 (CA-Pak1) and controls expressing LacZ; however, time to peak shortening was significantly faster and rate of [Ca²⁺]_i decay and time of relengthening were slower. Neither caffeine-releasable sarcoplasmic reticulum (SR) Ca²⁺ content nor fractional release was different in CA-Pak1 myocytes compared with controls. Isoproterenol application revealed a significantly blunted increase in [Ca²⁺]_i transient amplitude, as well as a slowed rate of [Ca²⁺]_i decay, increased SR Ca²⁺ content, and increased cell shortening, in CA-Pak1 myocytes. We found no significant change in phospholamban phosphorylation at Ser¹⁶ or Thr¹⁷ in CA-Pak1 myocytes. Analysis of cardiac troponin I revealed a significant reduction in phosphorylated species that are primarily attributable to Ser^23/24 in CA-Pak1 myocytes. Nonstimulated, spontaneous SR Ca²⁺ release sparks were significantly smaller in amplitude in CA-Pak1 than LacZ myocytes. Propagation of spontaneous Ca²⁺ waves resulting from SR Ca²⁺ overload was significantly slower in CA-Pak1 myocytes. Our data indicate that CA-Pak1 expression has significant effects on ventricular myocyte contractility through altered myofilament Ca²⁺ sensitivity and modification of the [Ca²⁺]_i transient.

cardiac relaxation; phosphatase; sarcoplasmic reticulum