Protein Coupled Receptors That Regulate Ion Channels

As we learned in Chapter 7, many neurotransmitter receptors are ligand-gated ion channels. These include some types of glutamate and serotonin receptors, as well as the nicotinic acetylcholine receptor found at nerve-muscle synapses. Many neurotransmitter receptors, however, are G protein-coupled receptors. The effector protein for some of these is a Na+ or K+ channel; neurotransmitter binding to these receptors causes the associated ion channel to open or close, leading to changes in the membrane potential. Other neurotransmitter receptors, as well as odorant receptors in the nose and pho-toreceptors in the eye, are G protein-coupled receptors that indirectly modulate the activity of ion channels via the action of second messengers. In this section, we consider two G protein-coupled receptors that illustrate the direct and indirect mechanisms for regulating ion channels: the muscarinic acetylcholine and Gt-coupled receptors.

Cardiac Muscarinic Acetylcholine Receptors Activate a G Protein That Opens K+ Channels

Binding of acetylcholine to nicotinic acetylcholine receptors in striated muscle cells generates an action potential that triggers muscle contraction (see Figure 7-45). In contrast, the muscarinic acetylcholine receptors in cardiac muscle are inhibitory. Binding of acetylcholine to these receptors slows the

▲ FIGURE 13-21 Operational model of muscarinic acetylcholine receptor in the heart muscle plasma membrane.

These receptors are linked via a trimeric G protein to K+ channels. Binding of acetylcholine triggers activation of the Gia subunit and its dissociation from the Gp7 subunit in the usual way (see Figure 13-11). In this case, the released Gp7 subunit (rather than Gia GTP) binds to and opens the associated effector, a K+ channel. The increase in K+ permeability hyperpolarizes the membrane, which reduces the frequency of heart muscle contraction. Though not shown here, activation is terminated when the GTP bound to Gia is hydrolyzed to GDP and Gia GDP recombines with Gpr [See K. Ho et al., 1993, Nature 362:31, and Y Kubo et al., 1993, Nature 362:127]

rate of heart muscle contraction by causing a long-lived (several seconds) hyperpolarization of the muscle cell membrane. This can be studied experimentally by direct addition of acetylcholine to heart muscle in culture.

Activation of the muscarinic acetylcholine receptor, which is coupled to a Gi protein, leads to opening of associated K+ channels; the subsequent efflux of K+ ions causes hyperpolarization of the plasma membrane. As depicted in Figure 13-21, the signal from activated receptors is transduced to the effector protein by the released Gp7 subunit rather than by Ga-GTP. That Gp7 directly activates the K+ channel was demonstrated by patch-clamping experiments, which can measure ion flow through a single ion channel in a small patch of membrane (see Figure 7-17). When purified Gp7 protein was added to the cytosolic face of a patch of heart muscle plasma membrane, K+ channels opened immediately, even in the absence of acetylcholine or other neuro-transmitters.

Gt-Coupled Receptors Are Activated by Light

The human retina contains two types of photoreceptors, rods and cones, that are the primary recipients of visual stimulation. Cones are involved in color vision, while rods are stimulated by weak light like moonlight over a range of wavelengths. The photoreceptors synapse on layer upon layer of interneurons that are innervated by different combinations of photoreceptor cells. All these signals are processed and interpreted by the part of the brain called the visual cortex.

Rhodopsin, a G protein-coupled receptor that is activated by light, is localized to the thousand or so flattened membrane disks that make up the outer segment of rod cells (Figure 13-22). The trimeric G protein coupled to rhodopsin, often called transducin (G), is found only in rod cells. A human rod cell contains about 4 X 107 molecules of rhodopsin, which consists of the seven-spanning protein opsin to which is covalently bound the light-absorbing pigment 11-cis-retinal. Upon absorption of a photon, the retinal moiety of rhodopsin is very rapidly converted to the all-trans isomer, causing a conformational change in the opsin portion that activates it (Figure 13-23). This is equivalent to the con-formational change that occurs upon ligand binding by other G protein-coupled receptors. The resulting form in which opsin is covalently bound to all-trans-retinal is called meta-rhodopsin II, or activated opsin. Analogous to other G protein-coupled receptors, this light-activated form of rhodopsin interacts with and activates an associated G protein (i.e., Gt). Activated opsin is unstable and spontaneously dissociates into its component parts, releasing opsin and all-trans-retinal, thereby terminating visual signaling. In the dark, free all-trans-retinal is converted back to 11-cis-retinal, which can then rebind to opsin, re-forming rhodopsin.

In the dark, the membrane potential of a rod cell is about — 30 mV, considerably less than the resting potential (—60 to

Acetylcholine

Cytosol

Active muscarinic ^-lDL

acetylcholine receptor

Acetylcholine

Active muscarinic ^-lDL

acetylcholine receptor

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