A hypothesis for the mechanism of receptor and G-protein-dependent enhancement of vascular smooth muscle myofilament Ca2+ sensitivity.
Agonist activation enhances smooth muscle myofilament Ca2+ sensitivity. The increased force accompanying receptor stimulation (over Ca2+ alone) requires GTP and is reversed by GDP beta S, demonstrating a G-protein dependence. Protein kinase C (PKC) activators, such as phorbol esters, mimic and PKC inhibitors block the agonist-induced increase in Ca2+ sensitivity, suggesting a role for PKC in the regulation of Ca2+ sensitivity. Myosin light chain (MLC) phosphorylation levels are transiently increased by agonist stimulation, but steady-state levels of MLC phosphorylation are similar to those in response to Ca2+ alone. Thus, G-protein-mediated inhibition of MLC phosphatase may account for the initial increase in force development but not the increase in steady-state force. In contrast to MLC, calponin phosphorylation levels are maintained during agonist stimulation of intact vascular smooth muscle. We propose that stimulation of smooth muscle by membrane depolarization increases MLC phosphorylation, but as a result of inhibition by unphosphorylated calponin only a portion of the phosphorylated cross bridges attach to actin. Agonist stimulation produces the same steady-state level of MLC phosphorylation but also leads to calponin phosphorylation via a PKC-dependent pathway. Thus, during agonist stimulation, all phosphorylated cross bridges can interact with actin, thereby generating significantly greater levels of force.
Rokolya
A
A
Bockus Research Institute, Graduate Hospital, Philadelphia, PA 19146, USA.
Ahn
H Y
HY
Moreland
S
S
van Breemen
C
C
Moreland
R S
RS
D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism*
D011956:Receptors, Cell Surface; D019204:GTP-Binding Proteins; D002118:Calcium