New insights into beta-adrenoceptors in smooth muscle: distribution of receptor subtypes and molecular mechanisms triggering muscle relaxation

Abstract

1. The beta-adrenoceptor is currently classified into beta(1), beta(2) and beta(3) subtypes and all three subtypes are expressed in smooth muscle. Each beta-adrenoceptor subtype exhibits tissue-specific distribution patterns, which may be a determinant controlling the mechanical functions of corresponding smooth muscle. Airway and uterine smooth muscles abundantly express the beta(2)-adrenoceptor, the physiological significance of which is established as a fundamental regulator of the mechanical activities of these muscles. Recent pharmacomechanical and molecular approaches have revealed roles for the beta(3)-adrenoceptor in the gastrointestinal tract and urinary bladder smooth muscle. 2. The beta-adrenoceptor is a G(s)-protein-coupled receptor and its activation elevates smooth muscle cAMP. A substantial role for a cAMP-dependent mechanism(s) is generally believed to be the key trigger for eliciting beta-adrenoceptor-mediated relaxation of smooth muscle. Downstream effectors activated via a cAMP-dependent mechanism(s) include plasma membrane K(+) channels, such as the large-conductance, Ca(2+)-activated K(+) (MaxiK) channel. 3. Beta-Adrenoceptor-mediated relaxant mechanisms also include cAMP-independent signalling pathways. This view is supported by numerous pharmacological and electrophysiological lines of evidence. In airway smooth muscle, direct activation of the MaxiK channel by G(s)alpha is a mechanism by which stimulation of beta(2)-adrenoceptors elicits muscle relaxation independently of the elevation of cAMP. 4. The cAMP-independent mechanism(s) is also substantial in beta(3)-adrenoceptor-mediated relaxation of gastrointestinal tract smooth muscle. However, in the case of the beta(3)-adrenoceptor, a delayed rectified K(+) channel rather than the MaxiK channel seems to mediate, in part, cAMP-independent relaxant mechanisms. 5. In the present article, we review the distribution of beta-adrenoceptor subtypes in smooth muscle tissues and discuss the molecular mechanisms by which each subtype elicits muscle relaxation, focusing on the roles of cAMP and plasma membrane K(+) channels.