CAMP formation receptor

A critical component of the G-protein effector cascade is the hydrolysis of GTP by the activated a-subunit (GTPase). This provides not only a component of the amplification process of the G-protein cascade (63) but also serves to provide further measures of dmg efficacy. Additionally, the scheme of Figure 10 indicates that the coupling process also depends on the stoichiometry of receptors and G-proteins. A reduction in receptor number should diminish the efficacy of coupling and thus reduce dmg efficacy. This is seen in Figure 11, which indicates that the abiUty of the muscarinic dmg carbachol [51 -83-2] to inhibit cAMP formation and to stimulate inositol triphosphate, IP, formation yields different dose—response curves, and that after receptor removal by irreversible alkylation, carbachol becomes a partial agonist (68). 

Stimulation and inhibition of the enzyme by the GPCR-G-protein cycle occur by analogous mechanisms. Agonists induce hormone receptors to increase a Ga-GDP-GTP exchange and subsequent Ga 3y dissociation (GDP-a py + GTP GTP-ax + [3y + GDP) (Fig. 4). Consequently, agents that affect either the dissociation of either G or Gs, or the association of their respective as, a , or (3y subunits with adenylyl cyclase could affect rates of cAMP formation in enzyme preparations or in intact cells and tissues. There are several important examples. Gas is stably activated by poorly hydrolyzable analogs of GTP, e.g. GTPyS... 

The 5-HTx receptor class comprises five receptors (5-HT1a, 5-HT1b, 5-HTiD, 5-ht1E> and 5-HT1F) which, in humans, share 40-63% overall sequence identity and couple somewhat preferentially to Gi/o to inhibit cAMP formation (see Tables 1-3). The 5-htiE receptors are given a lower case appellation to denote that... 

HT4, 5-HTcAMP formation, yet they are regarded as distinct receptor classes because of their limited (<35%) overall sequence identities. This subdivision is arbitrary and may be subject to future modification. 

Inhibition of adenylyl cyclase by mAChR activation results in decreased cAMP formation. A decrease in cAMP is most apparent when adenylyl cyclase is stimulated, for example, by activation of adrenergic receptors... 

The 5-HT4, 5-hts and 5-HT7 receptors are coupled to the stimulation of adenylyl cyclase. 5-HT4, 5-htg and 5-HT7 receptors preferentially couple to the stimulation of adenylyl cyclase, increasing cAMP formation, via the Gs family of G proteins (see Chs 19 and 21). These receptors, however, share only >35% overall sequence homology. For this reason, they are classified as distinct receptor groups or classes and not subtypes of a family. The grouping of these receptors together is considered to be somewhat arbitrary and may be modified in the future. A lower-case appellation is used for the 5-ht6 receptor because a physiological role for these receptors in intact tissue has not been found [28]. 

Adenylyl cyclases are regulated by Gas and Ga. Each of the different forms of adenylyl cyclase can be stimulated by activated Gas (i.e. Gas bound to GTP). In this way Gas couples endocrine and neurotransmitter receptors that stimulate cAMP formation to adenylyl cyclases... 

There are also many neurotransmitter and hormone receptors that contribute to the fine control of cAMP formation by inhibition of adenylyl cyclase. The action of inhibitory receptors is mediated by several different forms of the Gai family, specifically the Gail, Gai2, Gai3, Gao and Goa subtypes. The Ga subunits of these isoforms can inhibit the catalytic activity of adenylyl cyclase when the enzyme is activated by either Gas or forskolin. The inhibition of catalytic activity does not occur via competition with Gas but appears to occur by an interaction at a symmetric site on the AC molecule. Gai-mediated inhibition of adenylyl cyclase is most dramatic for AC5 and AC6. A few other forms of adenylyl cyclase, most notably AC1, can be inhibited by Gao but this effect is not as potent as the inhibition of AC5 and AC6 by Gai isoforms. The GTPase activity of Gai family members can be accelerated by a large family of RGS proteins (see Chapter 19). 

While the schemes for regulation are hypothetical, certain features do suggest different patterns of regulation of cAMP formation in cells that are consistent with the different forms of adenylyl cyclase expressed in the cell, or their phenotype. For example, in cells that contain AC1, AC3 or AC8 (Fig. 21-4A), cAMP formation would be stimulated by extracellular signals that activate receptors coupled to Gas as well as by those signals that increase Ca2+ entry into the cells. Neurons expressing AC1 may... 

A. The salutary effect of p-blockers appears to be due solely to its binding to the -receptor, which prevents norepinephrine binding and stimulates cAMP formation. The other choices do not occur. 

Five subtypes of dopamine receptors have been described they are the Dj-like and Dj-like receptor groups. All have seven transmembrane domains and are G protein-coupled. The Dj-receptor increases cyclic adenosine monophosphate (cAMP) formation by stimulation of dopamine-sensitive adenylyl cyclase it is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The other member of this family is the D5-receptor, which also increases cAMP but has a 10-fold greater affinity for dopamine and is found primarily in limbic regions. The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding to the Dj-receptor. 

The primary effect of ACTH seems to be mediated via cAMP production by interaction of the hormone with differing populations of receptors. The difference between the extent of steroidogenesis and cAMP formation indicates different receptor affinities in different organs. 

The diverse actions of AM are mediated by the 7-transmembrane G protein-coupled calcitonin receptor-like receptor (CRLR) which coassembles with subtypes 2 and 3 of a family of receptor-activity-modifying proteins (RAMPs), thus forming a receptor-coreceptor system. Binding of AM to CRLR activates Gs and triggers cAMP formation in vascular smooth muscle cells, and increases nitric oxide production in endothelial cells. Other signaling pathways are also involved. 

In other cell types, guanine nucleotides interact with a guanine nucleotide subunit (G- or Ng-subunit) to translate receptor stimulation into increased adenylate cyclase activity (12.) Cholera toxin inhibits a specific GTPase on this guanine nucleotide subunit and thereby increases adenylate cyclase activity (13.). In dispersed cells from the bovine parathyroid gland, cholera toxin markedly increases cAMP formation and causes a 3 to 10-fold increase in the apparent affinity cf dopamine for its receptor (as determined by cAMP accumulation or IR-PTH secretion (J y.). The effects of guanine nucleotides and cholera toxin on cAMP accumulation in parathyroid cells result from interactions with the guanine nucleotide subunit in this cell. 

Ruat M, Traififort E, Leurs R, et al. Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation. Proc Natl Acad Sci USA 1993 90 8547-8551. 

Third, Berg et al. showed that the 5-HT2A receptor induces CaM-dependent increases in cAMP formation in A1A1 cells (201). Fourth, a CaM-dependent pathway is involved in 5-HT2A receptor-induced cyclo-oxygenase 2 mRNA expression in renal mesangial cells (202,203). 

The 5-HT2A receptor can regulate cAMP formation in certain cells, although this effect is cell-specific (220). In renal mesangial cells, the 5-HT2A receptor inhibits forskolin-stimulated cAMP formation through a pertussis toxin-sensitive mechanism (187). The inhibition of cAMP apparently occurs through direct interaction with Gi/o in that it was present in washed membranes and did not... 

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