REGULATION OF 2ND MESSENGERS ASSOCIATED WITH AIRWAY SMOOTH-MUSCLE CONTRACTION AND RELAXATION

Agonist-receptor interactions regulate airway smooth muscle tone throu gh activation of guanine nucleotide binding proteins (C proteins), whi ch are coupled to second messenger pathways that mediate changes in th e tissue's contractile state. With respect to airway smooth muscle (AS M) contraction, receptor activation elicits phosphatidylinositol turno ver that results in the formation of the second messengers, 1,2,-diacy lglyserol, which activates protein kinase C (PKC), and inositol 1,4,5, - trisphosphate (Ins[1,4,5]P-3), which binds to its intracellular rece ptor to mobilize intracellular calcium (Ca2+). Both the mobilization o f Ca2+ and activation PKC play critical roles in initiating and acutel y modulating the intensity and duration of the ASM contraction respons e. In contrast, bronchodilator agonist-mediated receptor activation is typically coupled to an enhanced accumulation of the second messenger , adenosine 3',5'-cyclic monophosphate (cAMP) which, through activatio n of cAMP-dependent protein kinase, induces the phosphorylation of spe cific proteins, leading to ASM relaxation. For activation of both of t hese functionally distinct signal transduction pathways, the agonist-r eceptor complexes interact with specific C proteins, which in turn mod ulate the enzymes regulating the production of their respective second messengers. Perturbations in Ins(1,4,5)P-3 accumulation, its metaboli sm and intracellular binding may underlie changes in ASM contractility . Comparably, changes in ASM relaxation responsiveness, secondary to p erturbations in cAMP accumulation, may be due to altered receptor/G pr otein modulation of adenylate cyclase activity, as well as to altered binding of Ins(1,4,5)P-3 to its Ca2+-mobilizing intracellular receptor . This review begins with an overview of the structural and functional characteristics of G protein-linked receptors, followed by descriptio ns of the role of G proteins, their transmembrane signaling processes, and mechanisms regulating second messenger-coupled ASM contraction an d relaxation, and concludes with new information underscoring the impo rtant roles of altered receptor/G protein-coupled expression and regul atory interactions between signaling pathways in modulating second-mes senger accumulation and action in the ''pro-asthmatic'' sensitized air way smooth muscle.