Effector Molecules of G Proteins

It is likely that phosducins play a role in many G-protein coupled signal transduction pathways. Phosducin-like proteins have been identified in a variety of tissues, e.g., in brain and in the pineal gland. 

Binding of phosducin to the Pycomplex leads to its translocation from the membrane into the cytosol. In this way, the number of Py-complexes available for the G-protein cycle is reduced and signal transmission is weakened. Interestingly, the phosdu-cin function is subject to regulation by phosphorylation. In the Ser-phosphorylated form, binding to the Py-complex is greatly weakened. 

The adenylyl cyclases catalyze the formation of 3 -5 -cychc AMP (cAMP) from ATP (Fig. 5.21). cAMP is a widespread signal molecule that primarily functions via activa- 

Despite the central importance of adenylyl cyclase for hormonal signal transduction, its structural and functional characterization is incomplete. In mammals, at least 9 dif- 

The adenylyl cyclases are large transmembrane proteins with a complex transmembrane topology. The assumed topology (Fig. 5.22) shows a short cytoplasmic N-termi-nal section followed by a transmembrane domain Ml with six transmembrane sections, and a large cytoplasmic domain Cl. The structural motif is repeated so that a second transmembrane domain M2 and a second cytoplasmic domain C2 can be differentiated. The complicated structure resembles the structure of some ATP-dependent membrane transport systems such as the P glycoprotein. A transport function has not yet been demonstrated for adenylyl cyclase. 

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The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

The Gt- and Gg-proteins are also classed as Gi-proteins, based on sequence homologies. The Gt- and Gg-proteins are involved in transmitting sensory signals. Signal transmission in the vision process is mediated via G-proteins known as transducins (Gt). The Gt-proteins are activated by the photoreceptor rhodopsin and are located in the rods and cones of the retina. The sequential effector molecules of the Gt-proteins are cGMP-specific phosphdiesterases (see Fig. 17.9). 

For the structural determination of the activated form of the a-subunit, use of A1F4 as a ligand was of great importance. AIF4 is an activator of GDP-bound a-sub-units and due to this characteristic — in addition to the bacterial toxins mentioned above — is often used for detection of G-proteins and for their structural characterization. In the presence of A1F4", permanent activation of the G-protein is observed G GDP is fixed by binding of AIF4 in a conformation that permits activation of the effector molecule. 

Ion chaimels can also be effector molecules in receptor-regulated signaling pathways (review Jan and Jan, 1997). The ion chaimel may be opened, for example, by direct interaction with a Gia subimit in the process of activation of G-protein-cou-pled receptors. 

McEntaffer, R. L., Natochin, M., and Artemyev, N. O. (1999). Modulation of transducin GTPase activity by chimeric RGS16 and RGS9 regulators of G protein signaling and the effector molecule. Biochemistry 38, 4931-4937. 

Starting from the activated receptor, a large number of reactions can be set in motion (Fig. 5.5). One main route of signal transmission takes place by activation of G proteins, another via activation of tyrosine-specific protein kinases, and a further route is via activation of ion channels. In the further course of G protein-mediated signal transmission, secondary diffusible signals are often formed the second messenger molecules (see Chapters 3 and 6). These function as effectors and activate further enzyme systems in the sequence, especially protein kinases. 

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