MODULATION OF THE CALCIUM SENSITIVITY OF THE SMOOTH-MUSCLE CONTRACTILE APPARATUS - MOLECULAR MECHANISMS, PHARMACOLOGICAL AND PATHOPHYSIOLOGICAL IMPLICATIONS

Smooth muscle contraction is the basis of the physiological reactivity of several systems (vascular, respiratory, gastrointestinal, urogenit al...). Hyperresponsiveness of smooth muscle may also contribute to a variety of problems such as arterial hypertension, asthma and spontane ous abortion. An increase in cytoplasmic calcium concentration ([Ca2+] (i)) is the key event in excitation-contraction coupling in smooth mus cle and the relationship linking the [Ca2+](i) value to the force of c ontraction represents the calcium sensitivity of the contractile appar atus (CaSCA). Recently, it has become evident that CaSCA can be modifi ed upon the action of agonists or drugs as well as in some pathophysio logical situations. Such modifications induce, at a fixed [Ca2+](i) va lue, either an increase (referred to as sensitization) or a decrease ( desensitization) of the contraction force. The molecular mechanisms un derlying this modulation are not yet fully elucidated. Nevertheless, r ecent studies have identified sites of regulation of the actomyosin in teraction in smooth muscle. Sensitization primarily results from the i nhibition of myosin light chain phosphatase (MLCP) by intracellular me ssengers such as arachidonic acid or protein kinase C. In addition, ph osphorylation of thin filament-associated proteins, caldesmon and calp onin, increases CaSCA. Activation of small (monomeric) G-proteins such as rho or ras is also involved. Desensitization occurs as a consequen ce of phosphorylation of myosin light chain kinase (MLCK) by the calci um-calmodulin activated protein kinase LI, or stimulation of MLCP by c yclic GMP-activated protein kinase. In the present review, examples of physiological modulation of CaCSA as well as pharmacological and path ophysiological implications are illustrated for some smooth muscles.