Guanylate Cyclase cGMP and Vascular Smooth Muscle

It is known that, once synthesized, gaseous NO readily diffuses in a heterotopic manner for "cellular" distances limited by its short half-life. A recent study using a photon counting camera reported actual visualization of NO release from electrically stimulated neurons [6]. Interestingly, NO was found to be released along the entire lengths of the neurons studied, confirming its ability to affect putative target cells in the three-dimensional space surrounding all parts of the releasing cell. In the vascular system, NO is released constitutively from endothelial cells and nervi vasorum, exerting its relaxant effect on neighbouring smooth muscle cells. Here, the principal molecular target for NO is the enzyme guanylate cyclase which, when activated by NO, converts guanosine triphos-phate (GTP) into cGMP. This so-called second messenger facilitates smooth muscle relaxation through hyperpolarization of the sarcolemma, involving activation of potassium channels and/or closure of voltage-dependent calcium channels, both of which are known to be modulated by NO in a variety of cell types. Although several mechanisms have been proposed to explain cGMP-evoked relaxation, the most likely mechanism may involve activation of cGMP-dependent protein kinase (protein kinase G; G-kinase; PKG), which leads to dephosphorylation of myosin light-chains (MLC) as well as activation of calcium- and voltage-dependent potassium channels in several cell types (Fig. 17.2). It should be noted that besides activating guanylate cyclase, NO can directly (i.e. independently of cGMP) modulate a variety of proteins, including potassium channels - an event which, when occurring in smooth muscle, leads to hyperpolarization and relaxation (Fig. 17.2).

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