G protein subunits

FIGURE 3.13 Major components of the cubic ternary complex model [25-27]. The major difference between this model and the extended ternary complex model is the potential for formation of the [ARjG] complex and the [RiG] complex, both receptor/ G-protein complexes that do not induce dissociation of G-protein subunits and subsequent response. Efficacy terms in this model are a, y, and 5. 

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... 

Recombinant systems can also be engineered to produce receptor-mediated responses by introducing adjunct proteins. For example, it has been shown that the Gal6 G-protein subunit couples universally to nearly all... 

CC, and one CX3C and XC chemokine receptors have been cloned so far [2]. Receptor binding initiates a cascade of intracellular events mediated by the receptor-associated heterotrimeric G-proteins. These G-protein subunits trigger various effector enzymes that lead to the activation not only of chemotaxis but also to a wide range of fimctions in different leukocytes such as an increase in the respiratory burst, degranulation, phagocytosis, and lipid mediator synthesis. 

The current understanding on activation of Tec kinases fits into a two-step model. In the first step an intramolecular interaction between the SH3 domain and aproline-rich region in the TH domain is disrupted by binding ofthe PH domain to phosphoinositides, G protein subunits, or the FERM domain of Fak. These interactions lead to conformational changes of Tec and translocation to the cytoplasmic membrane where, in a second step, Src kinases phosphorylate a conserved tyrosine residue in the catalytic domain thereby increasing Tec kinase activity. Autophosphorylation of a tyrosine residue in the SH3 domain further prevents the inhibitory intramolecular interaction resulting in a robust Tec kinase activation. 

The physiologic LRG interaction actually involves at least five types of components ligand, receptor, intact G or G protein subunits (a and Py), GTP (which promotes LRG dissociation and activation), and GDP (which promotes LR dissociation from G but not G dissociation into its subunits). Little about the dynamics of these processes is known. The LRG states may be visualized, in shorthand, as a 3-dimensional array (Figure 1). A large number of questions concerning LRG states remain to be addressed ... 

Ryba N. and Tirindelli R. (1996). The G-protein subunit g-8 is expressed the developing axons of olfactory and vomeronasal neurons. Europ J Neurosci 8, 2388-2398. 

Ikeda, S. R. and Dunlap, K., Voltage-dependent modulation of N-type calcium channels role of G-protein subunits, Adv. Second Messenger Phosphoprotein Res., 33, 131-151, 1999. 

Law SF, Reisine T. Changes in the association of G protein subunits with the cloned mouse delta opioid receptor upon agonist stimulation. J Pharmacol Exp Ther 1997 281 1476-1486... 

Ruiz-Velasco, V. and Ikeda, S. R. (2001). Functional expression and FRET analysis of green fluorescent proteins fused to G-protein subunits in rat sympathetic neurons. J. Physiol. 537, 679-92. 

Since that time, over 35 heterotrimeric G protein subunits have been identified by a combination of biochemical and molecular cloning techniques [1-4]. In addition to G Gs and G , the other types of G protein in brain are designated G0, Golf, G, Gz, Gq and G 16. Moreover, for most of these G proteins, multiple subtypes show unique distributions in the brain and peripheral tissues. G proteins are now divided into four main categories (Table 19-1) the Gs family stimulates adenylyl cyclase the G family (which includes G0, G, Gz) can inhibit... 

Multiple interactions are also being demonstrated between the traditional second-messenger pathways and the MAPK cascades. Free (3y G protein subunits, generated upon activation of receptors coupled to the G family, lead to activation of the ERK pathway. The mechanism by which this occurs, which may involve an interaction between the subunits and Ras or Raf, is a subject of intensive research (see Ch. 19). In addition, increases in cellular Ca2+ concentrations lead to stimulation of the ERK pathway, apparently via phosphorylation by CaMKs of proteins, for example She and Grb, that link growth factor receptor tyrosine kinases to Ras. Activation of the... 

These cues are important in rearing, territorial, courtship and, in particular, sexual behaviors. The vomeronasal organ (VNO) is separate from the main epithelium in mammals, comprising a thin epithelial tissue within a bony capsule in the lateral wall of the nasal cavity. It is probably vestigial in humans. The VNO epithelium contains at least two populations of microvillar chemosensory neurons one is in the more apical aspects of the epithelium, while the other lies in the more basal region. These two populations of vomeronasal neurons (VNs) are defined by the differential expression of several genes. For example, the apical VNs express the G-protein subunit Ga, while the basal neurons express Ga0. Apical and basal VNs also... 

Abnormalities in G protein subunits/cAMP signaling pathway have been observed in bipolar disorder 897... 

The G a-subunit is critical to perpetuating the GPCR signal because it is the free a- and Py-subunits that activate effector proteins and ion channels, such as AC, guanylyl cyclase, phospholipases C and A, Ca and K+ channels (74). For example, while the activated G a tends to activate AC (75,76), the G-a tends to inhibit AC, and activated G a tends to activate phospholipase C-P (44,77). Variations in receptor structure can change the rate at which these G protein subunits are liberated. Enhanced or diminished receptor signaling can result from the disruption of these processes at any step. 

Tissue Variability of G Protein Subunits and GPCR Signaling... 

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