Stimulatory G-protein

The majority of GPCRs couple to three families of G protein alpha subunits which differ in their ability to activate three distinct primary signaling cascades. The stimulatory G-protein Gas, positively regulates the activity of adenylyl cyclase causing an increase of intracellular cAMP levels as second messenger. In... 

Glycine-atginine-glycine-aspartic acid serine-proline Gro Growth-related oncogene GRP Gastrin-related peptide Gs Stimulatory G protein GSH Glutathione (reduced)... 

There are different kinds of G-proteins. The trimeric G-proteins are used mainly with transmembrane receptors. They have three subunits, a, P, and y. The a subunit is the GTPase part, but it s kept in its GDP form when it is bound to the p-y subunits. When GTP is bound, the a-subunit is released as an activated G-protein. The activated G-proteins can stimulate some downstream enzyme (these are called stimulatory G-proteins, or Gs). However, some G-proteins may be inhibitory in their active form—they re called G, Whether the target protein is stimulated or inhibited will depend on the type of G-protein. 

Biochemical and molecular cloning studies indicate the existence of nine separate and unique forms of adenylyl cyclase (AC), which comprise a distinct enzyme family, referred to as AC1-AC9 [1, 2]. These members of the adenylyl cyclase superfamily are all membrane-bound. There is also an additional soluble form, sAC, that has catalytic activity similar to the others but is genetically the most divergent member of the family. All the membrane-bound forms of adenylyl cyclase are activated by the stimulatory G protein Gas (see Ch. 19), and all with the exception of AC9 are stimulated by forskolin. The soluble form sAC is not stimulated by either Gas or forskolin but is sensitive to bicarbonate levels. All known forms of... 

Figure 6.1. Regulation of adenylate cyclase activity by G-proteins. Occupancy of receptors such as the /3-adrenergic receptor result in the activation (+) of adenylate cyclase via coupling through stimulatory G-proteins (Gs). Alternatively, occupancy of receptors such as the 2-adrenergic receptor inhibit (-) adenylate cyclase via coupling through inhibitory G-proteins (Gj).

Figure 6.3. Mechanism of action of heterotrimeric G-proteins. Upon receptor occupancy, the Ga-subunit binds GTP in exchange for GDP, and then moves in the membrane until it encounters its target enzyme, shown here as adenylate cyclase (alternatively, a phospholipase). The activated target enzyme then becomes functional. Inherent GTPase activity within the a-subunit then hydrolyses bound GTP to GDP, and the a-subunit dissociates from its target enzyme (which becomes inactive) and rebinds the / - and ysubunits. Upon continued receptor occupancy, further catalytic cycles of GTP exchange and target enzyme activation may occur. The scheme shown is for a stimulatory G-protein (Got,), but similar sequences of events occur with inhibitory G-proteins (Gcx,) except that the interaction of the a-subunit with adenylate cyclase will result in its inhibition. The sites of action of pertussis and cholera toxins are shown.

Bastepe, M., Weinstein, L. S., Ogata, N., et al. (2004) Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc. Natl. Acad. Sci. U. S. A. 101, 14794-14799. 

Liu, J., Erlichman, B., and Weinstein, L. S. (2003) The stimulatory G protein alpha-subunit Gs alpha is imprinted in human thyroid glands implications for thyroid function in pseudohypoparathyroidism types lA and IB. J. Clin. Endocrinol. Metab. 88, 4336-4341. 

G proteins are divided into several types, depending on their effects. Stimulatory G proteins (Cs) are widespread. They activate adenylate cyclases (see below) or influence ion channels. Inhibitory G proteins (Cj) inhibit adenylate cyclase. G proteins in the Gq family activate another effector enzyme—phospholipase c (see p. 386). 

One of the best-characterized effectors and second messenger systems is the cAMP cascade that can be either activated or inhibited by neurotransmit-ter/neuropeptide receptors, including those implicated in anxiety/stress such as CRE Receptors that activate cAMP synthesis couple with the stimulatory G protein, Gsa, and those that inhibit this second messenger couple with the inhibitory G protein, Gia, and these either stimulate or inhibit adenylyl cyclase, the effector enzyme responsible for synthesis of cAMP (Duman and Nestler 1999). There are at least nine different forms of adenylyl cyclase that have been identified by molecular cloning, each with a unique distribution in the brain. The different types of adenylyl cyclase are activated by Gsa as well as the diterpene forskolin, but are differentially regulated by Gia, the Py subunits, Ca, and by phosphorylation. This provides for fine control of adenylyl cyclase enzyme activity and regulation by other effector pathways. 

The cAMP second messenger pathway. Key proteins include hormone receptors (Rec), a stimulatory G protein (Gs), catalytic adenylyl cyclase (AC), phosphodiesterases (PDE) that hydrolyze cAMP, cAMP-dependent kinases, with regulatory (R) and catalytic (C) subunits,... 

The effects of catecholamines are mediated by cell-surface receptors. Adrenoceptors are typical G protein-coupled receptors (GPCRs see Chapter 2). The receptor protein has an extracellular N-terminus, traverses the membrane seven times (transmembrane domains) forming three extracellular and three intracellular loops, and has an intracellular C-terminus (Figure 9-1). G protein-coupled receptors are coupled by G proteins to the various effector proteins whose activities are regulated by those receptors. Each G protein is a heterotrimer consisting of a, 3, and 7 subunits. G proteins are classified on the basis of their distinctive ct subunits. G proteins of particular importance for adrenoceptor function include Gs, the stimulatory G protein of adenylyl cyclase Gj and G0, the inhibitory G... 

FIGURE 12-12 Transduction of the epinephrine signal the /J-adrenergic pathway. The seven steps of the mechanism that couples binding of epinephrine (E) to its receptor (Rec) with activation of adenylyl cyclase (AC) are discussed further in the text. The same adenylyl cyclase molecule in the plasma membrane may be regulated by a stimulatory G protein (Gs), as shown, or an inhibitory G protein (G, not shown). Gs and G, are under the influence of different hormones. Hormones that induce GTP binding to G, cause inhibition of adenylyl cyclase, resulting in lower cellular [cAMP]. 

The /3-adrenergic receptor binds epinephrine, then through a stimulatory G protein, Gs, activates adenylyl cyclase in the plasma membrane. The cAMP produced by adenylyl cyclase is an intracellular second messenger that stimulates cAMP-dependent protein kinase, which mediates the effects of epinephrine by phosphorylating key proteins, changing their enzymatic activities or structural features. 

Fig. (9). A) Schematical representation of the activation of intact adenylate cyclase (AC) b forskolin and Gsa (GTP- bound stimulatory G protein a subunit). Mammalian ACs consists o 12 transmembrane helices and two cytoplasmic catalytic domains (referred to as Q and C2 represented as lightly shaded and black respectively), (a) Hypothetical basal state, (b) Th suggested forskolin-activated state, (c) Forskolin and GSa-activated state.

Iltzsch, M.H., Bieber, D., Vijayasarathy, S., Webster, P., Zurita, M., Ding, J. and Mansour, T.E. (1992) Cloning and characterization of a cDNA coding for the a-subunit of a stimulatory G protein from Schistosoma mansoni. Journal of Biological Chemistry 267, 14504-14508. 

Receptors with lie at position 164 exhibit sustained, markedly dysfunctional properties with altered high affinity binding and decreased coupling to the stimulatory G protein in transfected cells (31,137), but the rarity of this polymorphism has so far precluded its study in the homozygous state or in situations of clinical interest. 

Already, we know the physiological response to chronic GPCR activation is cardiac arrhythmia bradycardia or tachycardia depending on whether the G-protein is stimulatory (Gees) or inhibitory (Gcd, GPy) (Redfern et al. 1999 Gehrmann et al. 2002 Hardt et al. 2002 Zhai et al. 2005 Nishizawa et al. 2006). A stimulatory G-protein results in an increase of intracellular calcium, while an inhibitory... 

The sympathetic nervous system plays a central role in regulating heart function and response to most types of stress through p-AR stimulation. Binding of p-adrenergic agonists to receptors in the heart activates adenylyl cyclase (AC) via a stimulatory G protein. On the other hand, it is known that the altered responses of the... 

Adenylate cyclase is a two-component enzyme system. It ultimately catalyzes the cyclase reaction, but only when it is associated with the hormone-bound receptor and a regulatory protein called a stimulatory G-protein (guanylate nucleotide binding protein), which activates adenylate cyclase. The G-protein is the intermediate between the receptor and the synthesis of cyclic AMP. 

Wiersbitzky M, Mills I, Sumpio BE, Gewirtz H. Chronic cyclic strain reduces adenylate cyclase activity and stimulatory G protein subunit levels in coronary smooth muscle cells. Exp Cell Res. 1994 210 52-55. 

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