NO activates soluble guanylate cyclase (sGC)

8. Pharmacology of nitric oxide

NO activates soluble guanylate cyclase (sGC)
  • Signaling effects of cGMP
  • NO-induced relaxation of smooth muscle cells is mediated by cGK
NO activates soluble guanylate cyclase (sGC)

Between the last slide and this one, we have skipped an important step, namely the diffusion of NO from the cell of origin, for example an endothelial cell, to another one, such as a vascular smooth muscle cell. Like other small gas molecules, nitric oxide passes through cell membranes with ease, which enables it to directly and rapidly interact with intracellular targets.

Within its target cell, NO binds to the heme group of soluble guanylate cyclase (sGC), dislodging a strategic histidine residue. This causes a conformational change that activates the enzyme, which then begins to make cyclic GMP (cGMP). The production of cGMP as a second messenger is the most important signal downstream of NO.

8.4.1 Signaling effects of cGMP
Signaling effects of cGMP

Like cAMP, cGMP targets multiple effector molecules inside the cell. Activation of cGMP-dependent protein kinases (cGK) is the most important single mechanism. Phosphodiesterase 5 (PDE) is activated, too, reducing the levels of both cAMP and cGMP. Actuation of cyclic nucleotide-gated cation channels affects the membrane potential and the cellular calcium level.

Membrane-bound receptor or “particulate” guanylate cyclases (pGC) provide an alternate means of cGMP production that is independent of NO but instead is controlled by several peptide hormones.

8.4.2 NO-induced relaxation of smooth muscle cells is mediated by cGK
NO-induced relaxation of smooth muscle cells is mediated by cGK

The relaxation of smooth muscle that occurs downstream of endothelial NO release is mediated by cGMP-dependent protein kinase. This kinase phosphorylates and thereby activates myosin light chain phosphatase. The phosphatase dephosphorylates myosin, which interrupts interaction of myosin with actin and induces relaxation.

cGK also phosporylates a regulatory subunit of the IP3 receptor channel. As we have seen before (slide 5.3.2), this channel mediates the outflow of Ca++ from the ER to the cytosol. Phosphorylation of the IP3 channel reduces Ca++ flow and therefore the calmodulin-dependent activation of myosin light chain kinase (MLCK).

It is worth noting that the effects of NO cut in below the GPCRs that mediate the effects of major vasoconstrictors such as angiotensin and norepinephrine. Therefore, NO-releasing drugs offer a means to interrupt the out-of-control signaling by such mediators that occurs in hemodynamic shock or hypertensive crisis.

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