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PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON

Increased Rho activation and PKC-mediated smooth muscle contractility in the absence of caveolin-1

¹Department of Experimental Medical Science, Lund University, ²Department of Otorhinolaryngology, Malmö University Hospital, and ³Department of Physiology and Pharmacology, Karolinska Institute, Stockholm

Submitted 1 February 2006 ; accepted in final form 18 July 2006

Caveolae are omega-shaped membrane invaginations that are abundant in smooth muscle cells. Since many receptors and signaling proteins co-localize with caveolae, these have been proposed to integrate important signaling pathways. The aim of this study was to test whether RhoA/Rho-kinase and protein kinase C (PKC)-mediated Ca²⁺ sensitization depends on caveolae using caveolin (Cav)-1-deficient (KO) and wild-type (WT) mice. In WT smooth muscle, caveolae were detected and Cav-1, -2 and -3 proteins were expressed. Relative mRNA expression levels were 15:1:1 for Cav-1, -2, and -3, respectively. Caveolae were absent in KO and reduced levels of Cav-2 and Cav-3 proteins were seen. In intact ileum longitudinal muscle, no differences in the responses to 5-HT or the muscarinic agonist carbachol were found, whereas contraction elicited by endothelin-1 was reduced. Rho activation by GTPS was increased in KO compared with WT as shown using a pull-down assay. Following -toxin permeabilization, no difference in Ca²⁺ sensitivity or in Ca²⁺ sensitization was detected. In KO femoral arteries, phorbol 12,13-dibutyrate (PDBu)-induced and PKC-mediated contraction was increased. This was associated with increased ₁-adrenergic contraction. Following inhibition of PKC, ₁-adrenergic contraction was normalized. PDBu-induced Ca²⁺ sensitization was not increased in permeabilized femoral arteries. In conclusion, Rho activation, but not Ca²⁺ sensitization, depends on caveolae in the ileum. Moreover, PKC driven arterial contraction is increased in the absence of caveolin-1. This depends on an intact plasma membrane and is not associated with altered Ca²⁺ sensitivity.

Ca²⁺ sensitization; Rho-associated kinase; myosin phosphatase target protein; lipid rafts; CPI-17; G protein-coupled receptor

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