Adenylate Cyclase-Dependent Signaling

The second popular hypothesis for the therapeutic mechanism of action of Li+ is its interference with another receptor-coupled, second messenger system, that of the plasma-membrane bound enzyme, adenylate 

The effects of Li+ upon this system have been reviewed in depth by Mork [131]. Animal studies originally demonstrated that Li+ inhibits cAMP formation catalyzed by adenylate cyclase in a dose-dependent manner [132]. The level of cAMP in the urine of manic-depressive patients changes with mental state, being abnormally elevated during the switch period between depression and mania it is proposed that Li+ s inhibitory effect upon adenylate cyclase activity may correct this abnormality. Subsequent research, in accord with the initial experiments, have shown that Li+ s interference with this second messenger system involves more than one inhibitory action. At therapeutic levels, Li+ inhibits cAMP accumulation induced by many neurotransmitters and hormones, both in 

at therapeutically relevant concentrations, is a potent inhibitor of norepinephrine-stimulated adenylate cyclase activity ex vivo in both rat [133] and human brain [134], and it inhibits norepinephrine-stimulated cAMP accumulation in Li+-treated patients. Li+ also inhibits dopamine-stimulated cAMP accumulation in rat brain [135]. These inhibitory effects of Li+ have been shown to be region specific within rat brain, a fact that has obvious significance for a therapeutic mechanism of action. It is interesting that other antimanic drugs may also have dampening effects on dopaminergic neurotransmission. 

Li+ also inhibits several hormone-stimulated adenylate cyclases which, in some cases, appear to be related to side effects of Li+ therapy. For instance, Li+ inhibits the hydro-osmotic action of vasopressin, the antidiuretic hormone which increases water resorption in the kidney [136]. This effect is associated with polyuria, a relatively harmless side effect sometimes experienced with Li+ treatment, which arises from the inability of the kidney to concentrate urine. Li+ has been shown to inhibit vasopressin-stimulated adenylate cyclase activity in renal epithelial cells. Additionally, Li+ is reported to enhance the vasopressin-induced synthesis of prostaglandin E2 (PGE2) in vitro in kidney. PGE2 inhibits adenylate cyclase activity by stimulation of Gj, and, therefore, this effect may contribute to the Li+-induced polyuria. 

Mg2+ is competitive with the Li+ inhibition of both postreceptor G-protein stimulation [140], and direct stimulation of adenylate cyclase [141]. Li+ inhibits Mn2+-stimulated adenylate cyclase activity in membranes in the presence, but not in the absence, of calmodulin. Since, Mn2+ can replace Ca2+ in activating calmodulin, it is likely that the observed inhibition is that of the Mn2+-dependent calmodulin stimulation of the enzyme. In the absence of calmodulin, stimulation of adenylate cyclase is probably due to substitution of Mn2+ for Mg2+ in the substrate, MnATP2+ and this is unaffected by Li+. 

---

H2 receptors are associated with adenylate cyclase, and stimulation of these receptors increases the cytosolic concentration of cAMP and activation of cAMP-dependent protein kinase. Although inhibition of adenylate cyclase has been suggested as the intracellular signaling mechanism associated with H receptors, this has not been completely substantiated. 

Some signal pathways that activate the adenylate cyclase phosphorylate tyrosine residues (Y535) of the TAF2 domain, which, as previously mentioned, is dependent on hormone binding. In this case, modulation of the transcription... 

Figure 14-2. Regulation of cyclic AMP-dependent protein kinase A (PKA) by cyclic AMP. Activation of adenylate cyclase by binding of G( -GTP amplifies the signal by synthesis of many molecules of cyclic AMP. Cyclic AMP binding to PKA causes dissociation of the regulatory subunits from the catalytic subunits, which carry on the signal. Phosphodiesterase regulates the concentration of cyclic AMP by catalyzing its hydrolysis to AMP, which shuts off the signal.

It is well know that /3-adrenoceptors couple to adenylate cyclases to activate a protein kinase A (PKA), but no direct evidence exists for the involvement of the /3-adrenoceptor-PKA signaling pathway in the affective component of pain. Thus, we examined the effect of intra-vBNST administration of a selective PKA inhibitor on isoproterenol- and pain-induced aversion. CPA induced by the intra-vBNST injection of isoproterenol was reversed by the coinjection of Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS), a selective PKA inhibitor. Furthermore, intra-vBNST injection of Rp-cAMPS dose-dependently attenuated the F-CPA. These data suggest that PKA activation within the vBNST via the enhancement of /3-adrenergic transmission is important for the negative affective component of pain (Fig. 3). 

Following cannabinoid binding, multiple signaling pathways can be activated Gij0jS-protein mediated modulation of adenylate cyclase and cAMP levels Ca2+ and K+ ion channel activation or activation of different intracellular enzymes/effectors (i.e., kinases, ceramide) in a non-G-protein dependent manner (Childers et al., 1993 Felder et al., 1995 Mackie et al., 1995 Prather et al., 2000 Sanchez et al., 2001). 

---