Figure 15–39 The response of a rod photoreceptor cell to light. Rhodopsin molecules in the outer-segment discs absorb photons. Photon absorption closes cation channels in the plasma membrane, which hyperpolarizes the membrane and reduces the rate of neurotransmitter release from the synaptic region. Because the neurotransmitter inhibits many of the postsynaptic retinal neurons, illumination serves to free the neurons from inhibition and thus, in effect, excites them. The neural connections of the retina lie between the light source and the outer segment, and so the light must pass through the synapses and rod cell nucleus to reach the light sensors.
to Na+, so that when they close, the normal influx of Ca2+ is inhibited, causing the Ca2+ concentration in the cytosol to fall. The decrease in Ca2+ concentration stimulates guanylyl cyclase to replenish the cyclic GMP, rapidly returning its level to where it was before the light was switched on. A specific Ca2+-sensitive protein mediates the activation of guanylyl cyclase in response to the fall in Ca2+ levels. In contrast to calmodulin, this protein is inactive when Ca2+ is bound to it and active when it is Ca2+-free. It therefore stimulates the cyclase when Ca2+ levels fall following a light response.
Negative feedback mechanisms do more than just return the rod to its resting state after a transient light flash; they also help the rod to adapt, stepping down the response when the rod is exposed to light continuously. Adaptation, as we discussed earlier, allows the receptor cell to function as a sensitive detector of changes in stimulus intensity over an enormously wide range of baseline levels of stimulation. It is why we can see faint stars in a dark sky, or a camera flash in bright sunlight.
The various trimeric G proteins we have discussed in this chapter fall into four major families, as summarized in Table 15–3.
Signaling molecules like cyclic nucleotides and calcium are hydrophilic small molecules that generally act within the cell where they are produced. Some signaling molecules, however, are hydrophobic enough, small enough, or both, to pass readily across the plasma membrane and carry signals to nearby cells. An important and remarkable example is the gas nitric oxide (NO), which acts as a signal molecule in many tissues of both animals and plants.
In mammals, one of NO’s many functions is to relax smooth muscle in the walls of blood vessels. The neurotransmitter acetylcholine stimulates NO synthesis by activating a GPCR on the membranes of the endothelial cells that line the interior of the vessel. The activated receptor triggers IP3 synthesis and Ca2+ release (see Figure 15–29), leading to stimulation of an enzyme that synthesizes NO. Because dissolved NO passes readily across membranes, it diffuses out of the cell where it is produced and into neighboring smooth muscle cells, where it causes muscle relaxation and thereby vessel dilation (Figure 15–40). It acts only locally because it has a short half-life—about 5–10 seconds—in the extracellular space before oxygen and water convert it to nitrates and nitrites.
The effect of NO on blood vessels provides an explanation for the mechanism of action of nitroglycerine, which has been used for about 100 years to treat patients with angina (pain resulting from inadequate blood flow to the heart muscle). The nitroglycerine is converted to NO, which relaxes blood vessels. This reduces the workload on the heart and, as a consequence, reduces the oxygen requirement of the heart muscle.
NO is made by the deamination of the amino acid arginine, catalyzed by enzymes called NO synthases (NOS) (see Figure 15–40). The NOS in endothelial cells is called eNOS, while that in nerve and muscle cells is called nNOS. Both eNOS and nNOS are stimulated by Ca2+. Macrophages, by contrast, make yet another NOS, called inducible NOS (iNOS), that is constitutively active but synthesized only when the cells are activated, usually in response to an infection.