In some target cells, including smooth muscle cells, NO binds reversibly to iron in the active site of guanylyl cyclase, stimulating synthesis of cyclic GMP. NO can increase cyclic GMP in the cytosol within seconds, because the normal rate of turnover of cyclic GMP is high: rapid degradation to GMP by a phosphodiesterase constantly balances the production of cyclic GMP by guanylyl cyclase. The drug Viagra® and its relatives inhibit the cyclic GMP phosphodiesterase in the penis, thereby increasing the amount of time that cyclic GMP levels remain elevated in the smooth muscle cells of penile blood vessels after NO production is induced by local nerve terminals. The cyclic GMP, in turn, keeps the blood vessels relaxed and thereby the penis erect. NO can also signal cells independently of cyclic GMP. It can, for example, alter the activity of an intracellular protein by covalently nitrosylating thiol (–SH) groups on specific cysteines in the protein.
Figure 15–40 The role of nitric oxide (NO) in smooth muscle relaxation in a blood vessel wall. (A) Simplified cross section of a blood vessel, showing the endothelial cells lining the lumen and the smooth muscle cells around them. (B) The neurotransmitter acetylcholine stimulates blood vessel dilation by activating a GPCR—the muscarinic acetylcholine receptor—on the surface of endothelial cells. This receptor activates a G protein, Gq, thereby stimulating IP3 synthesis and Ca2+ release by the mechanisms illustrated in Figure 15–29. Ca2+ activates nitric oxide synthase, causing the endothelial cells to produce NO from arginine. The NO diffuses out of the endothelial cells and into the neighboring smooth muscle cells, where it activates guanylyl cyclase to produce cyclic GMP. The cyclic GMP triggers a response that causes the smooth muscle cells to relax, increasing blood flow through the vessel.
Despite the differences in molecular details, the different intracellular signaling pathways that GPCRs trigger share certain features and obey similar general principles. They depend on relay chains of intracellular signaling proteins and second messengers. These relay chains provide numerous opportunities for amplifying the responses to extracellular signals. In the visual transduction cascade, for example, a single activated rhodopsin molecule catalyzes the activation of hundreds of molecules of transducin at a rate of about 1000 transducin molecules per second. Each activated transducin molecule activates a molecule of cyclic GMP phosphodiesterase, each of which hydrolyzes about 4000 molecules of cyclic GMP per second. This catalytic cascade lasts for about 1 second and results in the hydrolysis of more than 105 cyclic GMP molecules for a single quantum of light absorbed, and the resulting drop in the concentration of cyclic GMP in turn transiently closes hundreds of cation channels in the plasma membrane (Figure 15–41). As a result, a rod cell can respond to even a single photon of light in a way that is highly reproducible in its timing and magnitude.
Likewise, when an extracellular signal molecule binds to a receptor that indirectly activates adenylyl cyclase via Gs, each receptor protein may activate many molecules of Gs protein, each of which can activate a cyclase molecule. Each cyclase molecule, in turn, can catalyze the conversion of a large number of ATP molecules to cAMP molecules. A similar amplification operates in the IP3 signaling pathway. In these ways, a nanomolar (10–9 M) change in the concentration of an extracellular signal can induce micromolar (10–6 M) changes in the concentration of a second messenger such as cAMP or Ca2+. Because these messengers function as allosteric effectors to activate specific enzymes or ion channels, a single extracellular signal molecule can alter many thousands of protein molecules within the target cell.