Cyclic GMP

Cyclic guanosine 30,50-monophosphate (cGMP) is formed from guanosine triphosphate by the enzyme guanylyl cyclase which is not coupled to G-protein receptors. Though considerably less versatile than cAMP, cGMP plays an analogous second messenger role in many cells, particularly in smooth muscle cells, in platelets, and in the rods and cones of the visual system where it has been most thoroughly studied. Absorption of a photon of light causes a conformational change in rhodopsin, the visual pigment in rod cells, in much the same way that other G-protein linked receptors are activated by ligands (see Chapter 51). Activation of rhodopsin causes the a subunit of the heterotrimeric G-protein, transducin, to exchange its bound GDP for GTP and to dissociate from the Py subunits. Instead of protein kinase, the catalytic component activated by transducin is a cyclic nucleotide phosphodiesterase that converts cyclic GMP to 5-GMP (Fig. 16). In the dark or resting state, cGMP binds to and activates cation channels in the membrane that allow sodium and calcium ions to enter. Activation of phosphodiesterase accelerates the hydrolysis of cGMP, lowering its concentration and allowing the channels to close. Closure of the channels changes the electrical properties of the cell membrane and the rate of neurotransmitter release. The decline in intracellular calcium concentration that results from closure of cGMP-gated cation channels de-inhibits guanylyl cyclase, and allows cGMP concentrations to return to the resting level.

In smooth muscle cells, guanylyl cyclase activity may either be an intrinsic component of some transmembrane receptors or reside in the cytosol as a soluble protein. Both the transmembrane and the soluble forms of guanylyl cyclase are directly stimulated by agonists without the intercession of G-proteins. Increased

Rhodopsin

Rhodopsin

FIGURE 16 Role of cGMP in photoreception. In the dark, cyclic GMP (cGMP) binds to cyclic nucleotide-gated channels, keeping them open, so that both sodium (Na+) and calcium (Ca2+) enter the cell. In response to a photon of light, rhodopsin induces an allosteric change in its associated G-protein, transducin (T), causing the a subunit to exchange GDP for GTP and dissociate from the Py subunits. The free a subunit binds to cyclic nucleotide phosphodiesterase (PDE) and stimulates the degradation of cGMP. Decreased cGMP concentrations favor release of the bound nucleotide and closure of the cGMP-gated channels.

FIGURE 16 Role of cGMP in photoreception. In the dark, cyclic GMP (cGMP) binds to cyclic nucleotide-gated channels, keeping them open, so that both sodium (Na+) and calcium (Ca2+) enter the cell. In response to a photon of light, rhodopsin induces an allosteric change in its associated G-protein, transducin (T), causing the a subunit to exchange GDP for GTP and dissociate from the Py subunits. The free a subunit binds to cyclic nucleotide phosphodiesterase (PDE) and stimulates the degradation of cGMP. Decreased cGMP concentrations favor release of the bound nucleotide and closure of the cGMP-gated channels.

formation of cGMP in these and other cells activates protein kinase G, which, like PKA, catalyzes the phosphorylation of serine and threonine residues in various regulatory proteins. In platelets, activation of protein kinase G prevents clot formation by interfering with a constellation of reactions that promote clotting. Cyclic GMP also activates phosphodiesterase in some cells, and at least some of its biological effects may be explained by accelerated degradation of cAMP.

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