CAMP generators

The other major receptor-coupled second messenger system on which lithium exerts significant effects is the cAMP generating system. Forn and Valdecasas (1971] were the first to report that lithium in vitro attenuated NE-stimulated cAMP accumulation since then, numerous studies have... 

Positive inotropic compounds can be classified into three groups cAMP generators, intracellular calcium regulators, and modulators of ion channels or pumps [11]. The cAMP generators such as dopamine, dobutamine, and milrinone (a phosphodiesterase inhibitor) may worsen ischemia, cause arrhythmias, and increase mortality [2,6]. Intracellular calcium modulators have not reached clinical use, possibly because of additional effects such as vasoconstriction,... 

Schematic diagram showing some of the potential sites of action of antidepressant drugs. Chronic therapy with these drugs has been proved to reduce reuptake of norepinephrine or serotonin (or both), reduce the number of postsynaptic Preceptors, and reduce the generation of cAMP. The MAO inhibitors act on MAO in the nerve terminals and cause the same effects on Preceptors and cAMP generation.

Lai NC, Roth DM, Gao MH, et al, Intracoronary delivery of adenovirus encoding adenylyl cyclase VI increases left ventricular function and cAMP-generating capacity, Circulation 2000 ... 

Fig. 4.6 cAMP generation in non-PC and PC hearts in response to isoproterenol and forskolin. Arrows indicate time of administration of the drugs. One series of hearts was reserpinized 24 hours before experimentation. p < 0.05. 

Fig. 2. A schematic representation of some of the mechanisms by which Car fluxes across the plasma membrane are regulated. In the plasma membrane (the striped area) there are both influx (=>) and energy-dependent ( ) efflux pathways. Two mechanisms by which Ca2+ influx can be increased are via the actions of the intracellular messengers inositol 1,3,4,5-tetrakisphosphate, and cAMP generated via activation of specific classes of surface receptors (R, and R2) linked to specific N proteins which activate either phosphatidylinositol 4,5-bisphosphate (PIP,) hydrolysis or adenylate cyclase (AC). Additionally, influx can be increased either by a direct receptor-coupled event or by a membrane depolarization (not shown). A rise in the Ca2+ concentration in the domain just beneath the plasma membrane, [Ca2+Isin, can lead to an activation of the Ca2+ pump either via a direct calmodulin (CaM)-dependent mechanism, or indirectly via the activation of protein kinase C (CK). Additionally, in some cells, an increase in cGMP concentration also increases Ca2+ efflux (not shown), and in still others cAMP may stimulate Ca2 efflux.

In contrast to, cA/VtP is unable to stimulate exocytosis on its own, but potentiates Ca -induced exocytosis (Vallar efal., 1987). This is consistent with the role of cAMP-generating hormones as potentiators of insulin secretion. 

EP, Receptors. EPg receptors are tcoupled to Gg and mediate increases in intra-Jcellular cAMP concentrations. Evidence fiDr this was first obtained by Hardcastle and co-fvrorkers, who reported a positive association Ibetween EP, and cAMP generation in entero- ( es (176) and more recently from recombi-Inant systems. 

Many other hormones alter lipolysis through their effect on catecholamine signaling, including alteration of P-adrenergic receptor levels, adenylyl cyclase activity, or inhibitory G-protein levels. All of these effects result in increased cAMP generation in the presence of catecholamines. The main hormones involved are glucocorticoids, chronic growth... 

Iodide by an Xl-type mechanism inhibits both cAMP and the phospholipase G cascades (Figure 32.2). The inhibition of TSH, prostaglandin El (PGEl), cholera toxin and forskolin-activated cAMP cascade bears on Gs— adenylyl cyclase couple and on cAMP generation (Gochaux et al, 1987 Filetti and Rapoport, 1983 ... 

Fig. 4. Translocation of CRAC-GFP in chemotactic Dictyostelium cells, (a) Response to a uniform stimulus of cAMP, generated as illustrated in Fig. 2a. Translocation occurs around the entire perimeter of the cell, (b) Directional response to a gradient of cAMP, generated as illustrated in Fig. 3a. The gradient direction is from bottom (low concentration) to top (high concentration). Translocation occurs preferentially at the side of the cell toward higher cAMP concentrations. Reproduced with permission from ref. 1. Copyright 2007 American Chemical Society.

Hormone induced cAMP generation in adipose tissue is very repid. One minute after addition of epinephrine to perfusate. Ho and Neng found elevated values (6). Lipolysis is stimulated to maximal rates within about 30 to 60 seconds after addition of glucagon to adipose tissue in vitro (7). This must mean that the hormone quickly equilibrates with its presumptive receptor sites. 

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