Cross talk between cyclic nucleotides and polyphosphoinositide hydrolysis,protein kinases, and contraction in smooth muscle

This article provides an update of a minireview published in 1996 (Abdel-La tif AA. Proc Soc Exp Biol Med 211:163-177, 1996), the purpose of which was to examine in nonvascular smooth muscle the biochemical and functional cros s talk between the sympathetic nervous system, which governs the formation of cAMP and muscle relaxation, and the parasympathetic nervous system, whic h governs the generation of IP3 and diacylglycerol, from the polyphosphoino sitides, Ca2+ mobilization, end contraction. This review examines further e vidence, both from nonvascular and vascular smooth muscle, for cross talk b etween the cyclic nucleotides, cAMP and cGMP via their respective protein k inases, and the Ca2+-dependent- and Ca2+-independent-signaling pathways inv olved in agonist-induced contraction. These include the IP3-Ca2+-CaM- myosi n light chain kinase (MLCK) pathway and the Ca2+-independent pathways, incl uding protein kinase C-, MAP kinase-, and Rho-kinase. In addition, MLC phos phorylation and contraction can also be increased by a decrease in myosin p hosphatase activity. A summary of the cross talk between the cyclic nucleot ides and these signaling pathways was presented. In smooth muscle, there ar e several targets for cyclic nucleotide inhibition and consequent relaxatio n, including the receptor, G proteins, phospholipase C-beta1-4 isoforms, IP 3 receptor, Ca2+ mobilization, MLCK, MAP kinase, Rho-kinase, and myosin pho sphatase. While significant progress has been made in the past four years o n this cross talk, the precise mechanisms underlying the biochemical basis for the cyclic nucleotide inhibition of Ca2+ mobilization and consequently muscle contraction remain to be established. Although it is well establishe d that second-messenger cross talk plays an important role in smooth muscle relaxation, the many sources which exist in smooth muscle for Ca2+ mobiliz ation, coupled with the multiple signaling pathways involved in agonist-ind uced contraction, contribute appreciably to the difficulties found by many investigators in identifying the targets for cyclic nucleotide inhibition a nd consequent relaxation. Better methodology and more novel interdisciplina ry approaches are required for elucidating the mechanism(s) of cAMP- and cG MP-inhibition of smooth muscle contraction.