G proteins types

Ga-GDP has no affinity for the effector protein and reassociates with the p and Y subunits (A). G-proteins can undergo lateral diffusion in the membrane they are not assigned to individual receptor proteins. However, a relation exists between receptor types and G-protein types (B). Furthermore, the a-subunits of individual G-proteins are distinct in terms of their affinity for different effector proteins, as well as the kind of influence exerted on the effector protein. G -GTP of the Gs-protein stimulates adenylate cyclase, whereas G -GTP of the Gr protein is inhibitory. The G-protein-coupled receptor family includes muscarinic cholinoceptors, adrenoceptors for norepinephrine and epinephrine, receptors for dopamine, histamine, serotonin, glutamate, GABA, morphine, prostaglandins, leukotrienes, and many other mediators and hormones. 

Mirotznik RR, Zheng X, Stanley EF (2000) G-Protein types involved in calcium channel inhibition at a presynaptic nerve terminal. J Neurosci 20 7614—21 Misonou H, Ohara-Imaizumi M, Kumakura K (1997) Regulation of the priming of exocytosis and the dissociation of SNAP-25 and VAMP-2 in adrenal chromaffin cells. Neurosci Lett 232 182—4 Misonou H, Ohara-Imaizumi M, Murakami T et al (1998) Protein kinase C controls the priming step of regulated exocytosis in adrenal chromaffin cells. Cell Mol Neurobiol 18 379-90... 

In most cases, it has been found that each member of an AR subfamily couples faithfully to a single G protein type. The arARs (a1A, a1B, a1D) act through Gq/11 to increase intracellular Ca2+, 0(2-ARs (o a, a2 S, oc ) act through G to decrease cAMP, and P-ARs (Pj, P2, P3) act through Gs to increase cAMP. The dual G protein specificity observed with other GPCRs, such as angiotensin II receptors (which activate both Gq/11 and G, families) (7), has not generally been observed with AR subtypes. 

Both types also interact with the p/y dimeric subunit of the G protein. Type 1 is inhibited and type 2 is activated in the presence of G the a subunit of a G, protein that transduces a signal for the stimulation of c-AMP production by adenylylcyclase. 

The muscarinic receptor is a seven-helix membrane-spanning G-protein-type receptor and the associated second messenger is either activation of inositol-3-phosphate (IPS) or inhibition of cyclic adenosine monophosphate (cAMP). There are five subtypes of the muscarinic receptors (M1-M5). All share the same general structure and the active site, but they differ in their tissue distribution, their second messenger mechanism and the associated physiological response. ... 

Several human receptors for the neurohypophyseal hormones have been cloned and the sequences elucidated. The human V2 receptor for antidiuretic hormone presumably contains 371 amino acids and seven transmembrane segments and activates cycHc AMP (76). The oxytocin receptor is a classic G-protein-coupled type of receptor with a proposed membrane topography also involving seven transmembrane components (84). A schematic representation of the oxytocin receptor stmcture within the membrane is shown in Eigure 4 (85). 

Finally, some amphiphilic sweeteners, eg, aspartame, saccharin, and neohesperidin dihydrochalcone, have been shown to be capable of stimulating a purified G-protein direcdy in an in vitro assay (136). This suggests some sweeteners may be able to cross the plasma membrane and stimulate the G-protein without first binding to a receptor. This type of action could explain the relatively longer response times and the lingering of taste associated with many high potency sweeteners. 

A variety of cellular and viral proteins contain fatty acids covalently bound via ester linkages to the side chains of cysteine and sometimes to serine or threonine residues within a polypeptide chain (Figure 9.18). This type of fatty acyl chain linkage has a broader fatty acid specificity than A myristoylation. Myristate, palmitate, stearate, and oleate can all be esterified in this way, with the Cjg and Cjg chain lengths being most commonly found. Proteins anchored to membranes via fatty acyl thioesters include G-protein-coupled receptors, the surface glycoproteins of several viruses, and the transferrin receptor protein. 

One target type for which the molecular mechanism of efficacy has been partly elucidated is the G-protein-coupled receptor (GPCR). It is known that activation of GPCRs leads to an interaction of the receptor with separate membrane G-proteins to cause dissociation of the G-protein subunits and subsequent activation of effectors (see Chapter 2). For the purposes of binding, this process can lead to an aberration in the binding reaction as perceived in experimental binding studies. Specifically, the activation of the receptor with subsequent binding of that... 

FIGURE 5.3 Different types of functional readouts of agonism. Receptors need not mediate cellular response but may demonstrate behaviors such as internalization into the cytoplasm of the cell (mechanism 1). Receptors can also interact with membrane proteins such as G-proteins (mechanism 2) and produce cytosolic messenger molecules (mechanism 3), which can go on to mediate gene expression (mechanism 4). Receptors can also mediate changes in cellular metabolism (mechanism 5). 

Cotecchia S et al (2004) Structural determinants involved in the activation and regulation of G protein-coupled receptors lessons from the ai -adrenergic receptor sub-types. Biol Cell 96 327-333... 

Recent studies indicate that - like many other receptors - G-protein-coupled receptors may form dimers, either homodimers or dimers with another type of receptor. The role of dimer formation in the cell surface expression of receptors and in their signalling and the resultant pharmacology are currently under intensive investigation [1]. 

Opioids act on heptahelical G-protein-coupled receptors. Three types of opioid receptors (p, 8, k) have been cloned. Additional subtypes (e.g., pl3 p2, 81 82), possibly resulting from gene polymorphisms, splice variants or alternative processing have been proposed. Opioid receptors are localized and can be activated... 

The cloned human GAL2 receptor binds porcine [125I]-[Tyr26]galanin and couples readily to Gq/Gn-type G proteins or related pathways in vitro. Under certain conditions, GAL2 also appears to couple with G/G0-and G12-type proteins [1, 2]. Specific examples of... 

Glutamate is a small amino acid which constitutes the most important neurotransmitter at excitatory synapses in the mammalian brain. Glutamate can act on several different types of receptors including cation channels and G-protein-coupled receptors. 

For differentiation of G-protein-coupled receptor sub-types from subtypes permanently linked to ion channels (ligand-gated ion channels) the terms metabotropic versus ionotropic receptors, respectively, are used. Prime examples of metabotropic receptors are given by the lnGlu receptor family of G-protein-coupled glutamate receptors. 

At a cellular level, the activation of mAChRs leads to a wide spectrum of biochemical and electrophysiological responses [1, 5]. The precise pattern of responses that can be observed does not only depend on the nature of the activated G proteins (receptor subtypes) but also on which specific components of different signaling cascades (e.g. effector enzymes or ion channels) are actually expressed in the studied cell type or tissue. The observed effects can be caused by direct interactions of the activated G protein(s) with effector enzymes or ion channels or may be mediated by second messengers (Ca2+, DP3, etc.) generated upon mAChR stimulation. 

The epithelium covering the nasal cavity. This epithelium contains numerous cell types including the specialized olfactory sensory neurons which detect the chemical stimuli derived from smells by a specific family of G protein-coupled receptors known as olfactory receptors. 

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