Cyclic nucleotide crosstalk and the regulation of cerebral vasodilation.
The vasodilating capability of cerebral vessels is vital to brain survival. There are multiple mechanisms participating in the regulation of cerebral vascular smooth muscle relaxation. The cyclic nucleotide-related signal transduction pathways are particularly important to the vasodilating function of cerebral arteries and arterioles. Those pathways are involved in the vasodilations elicited by a wide variety of stimuli, which include hypoxia and hypercapnia and agonist/receptor interactions (e.g. muscarinic, beta-adrenergic, and prostacyclin receptors). There is considerable control exerted upon the activities of the cyclic nucleotide signal transduction cascades. One of those control mechanisms relates to the abilities of cyclic 3'-5' adenosine monosphosphate (cAMP) and cyclic 3'-5' guanosine monophosphate (cGMP) to modulate each other's synthesis, degradation, and actions. That capacity for "crosstalk" between the two pathways provides the focus of the present review. To facilitate our discussion of cGMP/cAMP crosstalk regulation, we have placed some emphasis on hypercapnia-induced cerebral vasodilation. The review considers crosstalk at 4 different levels. First, the capacity for each cyclic nucleotide to repress the degradation of its counterpart via actions on phosphodiesterases (PDEs) is discussed. Second, consideration is given to crosstalk regulation of cGMP/cAMP synthesis. Third cGMP- or cAMP-dependent protein kinases (PKG and PKA, respectively) are discussed with respect to: (a) the potential of each cyclic nucleotide to activate the counterpart kinase, and (b) the ability of PKG: PKA to elicit common actions. Fourth, some attention is given to the role of compartmentalization of: (a) the enzymes catalyzing cyclic nucleotide synthesis and degradation, (b) the enzymes responsible for cyclic nucleotides-mediated phosphorylations, and (c) the protein targets of those kinases.
Department of Anesthesiology, University of Illinois at Chicago 60607, USA. dpell@uic.edu
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D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D014664:Vasodilation / Q000502:physiology*
D000242:Cyclic AMP; D011494:Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006152:Cyclic GMP