The pharmacology of phosducin

The discovery of phosducin (Phd) in photoreceptor cells of the retina and the further identification of phosducin-like proteins (PhdLP) emphasizes the existence of a family of proteins characterized as cytosolic regulators of G protein functions. The individual members represent phosphoproteins with distinct tissue distributions whose highest concentrations were in the retina and the pineal gland, while lower levels were reported for tissues such as liver, spleen, striated muscle, and the brain. Several functions of Phd and PhdLP have been suggested, but their most important ability appears to be their high affinity sequestration with G betagamma subunits of heterotrimeric G proteins. This finding suggests that neutralization of G betagamma by Phd effectively impedes G protein-mediated signal transmission, since G alpha cannot reassemble with G betagamma to provide a functional G protein trimer (G alphabetagamma). Thus, it is the scavenger quality of Phd that is hypothesized to diminish intracellular communication simply by reducing the number of G proteins. An additional important function of Phd relates to the inhibition of G alpha subunits' inherent GTPase. The ability of Phd to directly bind G alpha subunits is probably of minor significance as the affinity between both proteins is low. In general, similar mechanisms have been reported for PhdLPs. In the majority of investigations concerning the interference of Phd with physiological mechanisms, the dark/light adaptation of retinal photoreceptor cells has been the most frequently studied aspect of Phd. More recently, Phd was associated with the adenylyl cyclase of olfactory cilia, as in the presence of the phosphoprotein an increased concentration of cAMP is observed. This finding is in line with the experimental outcome of permanent cell lines transfected to overexpress Phd, which exhibit sensitization to excitatory acting PGE(1), and isoproterenol, respectively. Furthermore, Phd was found to effectively slow down the mechanism of internalization of G protein-coupled opioid receptors. Pathophysiological processes associated with Phd were found for certain eye diseases. Experimental evidence suggests the development of retinal inflammation as a consequence of an autoimmunization process triggered by Phd or shorter fragments thereof. Thus, our present knowledge regarding the functions of members of the Phd family is limited currently to their control of G protein-mediated intracellular signal transmission, the process of endocytosis, and certain autoimmune diseases of the uvea and the pineal gland. However, recent information regarding the presence of certain members of the Phd family in the cell nucleus may bear new insights into the function of these compounds.