Calcium dependent regulation of vascular smooth muscle contraction.

The experimental results discussed from our laboratory as well as from numerous other laboratories investigating the regulation of smooth muscle contraction have, in our opinion, clearly demonstrated that a simple Ca2+ dependent switch (MLC phosphorylation) cannot completely explain all of the mechanical and energetic findings. We and others have demonstrated that stress can be developed in the complete absence of increases in MLC phosphorylation, that crossbridge cycling rate can be regulated independent of changes in MLC phosphorylation, that Ca2+ can directly influence both stress and crossbridge cycling rate, and that protein kinase C can, apparently, directly initiate the development of stress supported by a specific population of crossbridges characterized by unphosphorylated MLC, low cycling rates, and weak binding characteristics. This information combined with the wealth of material demonstrating the important function played by the Ca2+ and calmodulin dependent MLC kinase is consistent with the hypothesis that there are two Ca2+ dependent regulatory systems acting in parallel in smooth muscle. One of these is the Ca2+ dependent MLC phosphorylation-dephosphorylation system responsible for the rapid development of stress and the second is a hypothesized Ca2+ dependent system responsible for the slow development of stress as well as the maintenance of previously developed stress. This second system has a higher Ca2+ sensitivity than that for MLC phosphorylation and may be activated by protein kinase C. The total stress attained by smooth muscle is activated by protein kinase C. The total stress attained by smooth muscle is the result of these two regulatory systems acting in concert. Although we believe the available information is consistent with this hypothesis of two regulatory systems functioning in parallel, it is by no means the only possibility. Early work from our laboratory and the recent work by the Somlyos and their colleagues and Kubota et al. suggest the possibility of a regulated MLC phosphatase which might functionally alter the Ca2+ sensitivity of the contractile filaments. Kerrick and Hoar and Nishimura and van Breemen have published data which imply a role for MgADP in latchbridge kinetics. These findings, as well as the discovery of several thin filament protein components which have been proposed as regulatory units, must all be taken into account in the final answer to the question: How does Ca2+ contract smooth muscle?