Excited Rhodopsin Acts through the G Protein Transducin to Reduce the cGMP Concentration

In its excited conformation, rhodopsin interacts with a second protein, transducin, which hovers nearby on the cytoplasmic face of the disk membrane (Fig. 12-33). Transducin (T) belongs to the same family of hetero-trimeric GTP-binding proteins as Gs and Gi. Although

FIGURE 12-32 Light-induced hyperpolarization of rod cells. The rod cell consists of an outer segment that is filled with stacks of membranous disks (not shown) containing the photoreceptor rhodopsin and an inner segment that contains the nucleus and other organelles. Cones have a similar structure. ATP in the inner segment powers the Na+K+ ATPase, which creates a transmembrane electrical potential by pumping 3 Na+ out for every 2 K+ pumped in. The membrane potential is reduced by the flow of Na+ and Ca2+ into the cell through cGMP-gated cation channels in the plasma membrane of the outer segment. When rhodopsin absorbs light, it triggers degradation of cGMP (green dots) in the outer segment, causing closure of the cation channel. Without cation influx through this channel, the cell becomes hyper-polarized. This electrical signal is passed to the brain through the ranks of neurons shown in Figure 12-31.

FIGURE 12-32 Light-induced hyperpolarization of rod cells. The rod cell consists of an outer segment that is filled with stacks of membranous disks (not shown) containing the photoreceptor rhodopsin and an inner segment that contains the nucleus and other organelles. Cones have a similar structure. ATP in the inner segment powers the Na+K+ ATPase, which creates a transmembrane electrical potential by pumping 3 Na+ out for every 2 K+ pumped in. The membrane potential is reduced by the flow of Na+ and Ca2+ into the cell through cGMP-gated cation channels in the plasma membrane of the outer segment. When rhodopsin absorbs light, it triggers degradation of cGMP (green dots) in the outer segment, causing closure of the cation channel. Without cation influx through this channel, the cell becomes hyper-polarized. This electrical signal is passed to the brain through the ranks of neurons shown in Figure 12-31.

Disk compartment

\ Rhodopsin

Disk compartment

\ Rhodopsin

Transducin

FIGURE 12-33 Likely structure of rhodopsin complexed with the G protein transducin. (PDB ID 1BAC) Rhodopsin (red) has seven transmembrane helices embedded in the disk membranes of rod outer segments and is oriented with its carboxyl terminus on the cytosolic side and its amino terminus inside the disk. The chromophore 11-c/s retinal (blue), attached through a Schiff base linkage to Lys256 of the seventh helix, lies near the center of the bilayer. (This location is similar to that of the epinephrine-binding site in the ^-adrenergic receptor.) Several Ser and Thr residues near the carboxyl terminus are substrates for phosphorylations that are part of the desensitization mechanism for rhodopsin. Cytosolic loops that interact with the G protein transducin are shown in orange; their exact positions are not yet known. The three subunits of transducin (green) are shown in their likely arrangement. Rhodopsin is palmitoylated at its carboxyl terminus, and both the a and y subunits of transducin have attached lipids (yellow) that assist in anchoring them to the membrane.

specialized for visual transduction, transducin shares many functional features with Gs and Gj. It can bind either GDP or GTP. In the dark, GDP is bound, all three subunits of the protein (Ta, T^, and Ty) remain together, and no signal is sent. When rhodopsin is excited by light, it interacts with transducin, catalyzing the replacement of bound GDP by GTP from the cytosol (Fig. 12-34, steps ©and ©). Transducin then dissociates into Ta and T^y, and the Ta-GTP carries the signal from the excited receptor to the next element in the transduction pathway, cGMP phosphodiesterase (PDE); this enzyme converts cGMP to 5'-GMP (steps ©and ©). Note that this is not the same cyclic nucleotide phosphodiesterase that hydrolyzes cAMP to terminate the ^-adrenergic response. The cGMP-specific PDE is unique to the visual cells of the retina.

PDE is an integral protein with its active site on the cytoplasmic side of the disk membrane. In the dark, a tightly bound inhibitory subunit very effectively suppresses PDE activity. When Ta-GTP encounters PDE, the inhibitory subunit is released, and the enzyme's activity immediately increases by several orders of magnitude. Each molecule of active PDE degrades many molecules of cGMP to the biologically inactive 5'-GMP, lowering [cGMP] in the outer segment within a fraction of a second. At the new, lower [cGMP], the cGMP-gated ion channels close, blocking reentry of Na+ and Ca2 + into the outer segment and hyperpolarizing the membrane of the rod or cone cell (step ©). Through this process, the initial stimulus—a photon—changes the Vm of the cell.

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