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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Convergence of Ca²⁺-desensitizing mechanisms activated by forskolin and phenylephrine pretreatment, but not 8-bromo-cGMP

Departments of ¹Biochemistry, ²Pediatrics, and ³Emergency Medicine, Virginia Commonwealth University School of Medicine, and ⁴Reanimation Engineering Shock Center, Virginia Commonwealth University, Richmond, Virginia

Submitted 21 October 2005 ; accepted in final form 17 January 2006

Contractile stimuli can sensitize myosin to Ca²⁺ by activating RhoA kinase (ROK) and PKC that inhibit myosin light chain phosphatase (MLCP) activity. Relaxant stimuli, acting through PKA and PKG (cyclic nucleotide-dependent protein kinases), and pretreatment with contractile agents such as phenylephrine (PE), can desensitize myosin to Ca²⁺. It is unknown precisely how these stimuli cause Ca²⁺ desensitization. To test the hypothesis that PKA, PKG, and PE pretreatment signaling systems converge to cause relaxation by inhibition of ROK in intact, isolated tissues, we examined the effects of forskolin (FSK; PKA activation), 8-bromo-cGMP (8br-cGMP; PKG activation), and PE pretreatment on KCl-induced force maintenance in rabbit arteries, a response nearly completely dependent on ROK activation. PE pretreatment and agents activating PKA and PKG caused Ca²⁺ desensitization by inhibiting KCl-induced tonic force and MLC phosphorylation without inhibiting intracellular [Ca²⁺]. At pCa 5 in -escin-permeabilized muscle, FSK and 8b-cGMP accelerated the relaxation rate when tissues were returned to pCa 9, suggesting that both agents can elevate MLCP activity. However, a component of the Ca²⁺ desensitization attributed to PKG activation in intact tissues appeared to involve a MLC phosphorylation-independent component. Inhibition of KCl-induced tonic force by the ROK inhibitor, Y-27632, and by PE pretreatment, were synergistically potentiated by 8b-cGMP, but not FSK. FSK and PE pretreatment, but not 8b-cGMP, inhibited the KCl-induced increase in site-specific myosin phosphatase target protein-1 phosphorylation at Thr⁸⁵³. These data support the hypothesis that PKA and PE pretreatment converge on a common Ca²⁺-desensitization pathway, but that PKG can act by a mechanism different from that activated by PKA and PE pretreatment.

vascular smooth muscle; Ca²⁺ sensitization; RhoA kinase; signal transduction

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