MODELS OF THE MECHANISM FOR CROSSBRIDGE ATTACHMENT IN SMOOTH-MUSCLE

The mechanism responsible for formation of attached, dephosphorylated crossbridges (latchbridges) in smooth muscle is controversial. Myosin light chain phosphorylation may be obligatory for crossbridge attachment; if this were the case, latchbridges would arise solely by dephosphorylation of attached, phosphorylated crossbridges. Alternatively, the presence of attached crossbridges could induce cooperative activation by allowing dephosphorylated crossbridges to attach to the thin filament. We evaluated whether four-state models based on dephosphorylation and/or cooperativity-regulated attachment could quantitatively predict smooth muscle contractile behaviour. Five quantitative models for transitions between crossbridge states were developed. Mechanisms for latchbridge formation included: (1) dephosphorylation, (2) cooperativity-regulated attachment dependent only on attached, phosphorylated crossbridges, (3) cooperativity-regulated attachment dependent on all attached crossbridges, (4) dephosphorylation and cooperativity-regulated attachment dependent only on attached, phosphorylated crossbridges, and (5) dephosphorylation and cooperativity-regulated attachment dependent on all attached crossbridges. All five models approximated the time course of contraction and the dependence of steady-state stress on myosin phosphorylation in the swine carotid artery. In the two models that had cooperative attachment regulated by all attached crossbridges, small increases in the rate constant for cooperativity-regulated attachment resulted in positive feedback and irreversible contraction. We suggest that a number of four-state crossbridge models can predict contractile behaviour in arterial smooth muscle. Potentially, latchbridges could be formed by both dephosphorylation and cooperativity-regulated attachment. If cooperativity-regulated latchbridge attachment does exist in smooth muscle, we suggest that it should be dependent only on the number of phosphorylated crossbridges rather than all attached crossbridges.