Adenylyl cyclase/cAMP system

Adenylyl-cyclase/cAMP system. Sutherland s studies revealed that the intracellular messenger cyclic 3, 5 -adenosine monophosphate (cyclic-AMP) is a nucleotide synthesized within the cell from ATP by the action of adenylyl-cyclase. Receptors linked to Gs activate adenylyl-... 

Multiple forms of heterotrimeric G proteins exist in the nervous system. Three types of heterotrimeric G protein were identified in early studies. G termed transducin, was identified as the G protein that couples rhodopsin to regulation of photoreceptor cell function (see Ch. 49), and Gs and G were identified as the G proteins that couple plasma membrane receptors to the stimulation and inhibition, respectively, of adenylyl cyclase, the enzyme that catalyzes the synthesis of cAMP (see Ch. 21). 

Adenylyl cyclases and the cAMP second messenger system... 

The noradrenergic neurons of the locus ceruleus have provided a useful model system for the study of opiate addiction (see Ch. 56). Acutely, opiates inhibit these neurons, in part by inhibiting the cAMP pathway via inhibition of adenylyl cyclase. Chronically, these neurons become tolerant to opiates that is, their firing rates recover toward normal levels with continued exposure to the... 

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 activation of adenylyl cyclase enables it to catalyze the conversion of adenosine triphosphate (ATP) to 3 5 -cyclic adenosine monophosphate (cAMP), which in turn can activate a number of enzymes known as kinases. Each kinase phosphorylates a specific protein or proteins. Such phosphorylation reactions are known to be involved in the opening of some calcium channels as well as in the activation of other enzymes. In this system, the receptor is in the membrane with its binding site on the outer surface. The G protein is totally within the membrane while the adenylyl cyclase is within the membrane but projects into the interior of the cell. The cAMP is generated within the cell (see Rgure 10.4). 

The pupils become dilated and there are associated signs of hyperactivity of the sympathetic nervous system, such as hypertension and pilomotor stimulation. The mechanism(s) underlying tolerance and dependence are poorly understood. While acute activation of Gi/o-coupled receptors leads to inhibition of adenylyl cyclase, chronic activation of such receptors produces an increase in cAMP accumulation, particularly evident upon withdrawal of the inhibitory agonist. This phenomenon, referred to as adenylyl cyclase superactivation, is believed to play an important role in opioid addiction. 

The biological effects of histamine (Table 15.1) are mediated via three receptor subtypes, HI, H2 and H3 that are linked to G protein but activate different cell-signalling systems. The histamine HI receptor is associated with the phospholipase C-catalysed formation of inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). The H2-receptor is coupled to adenylyl cyclase, increasing the production of cAMP. The cellular messenger system involved in H3-receptor activation has not been fully defined, but it may couple to N-type Ca2+-channels. The genes encoding for HI and H2 receptors have been cloned. A mutation of the human H2 receptor has been linked to schizophrenia. 

The effects of VIP are mediated by G protein-coupled receptors two subtypes, VPAC1 and VPAC2, have been cloned from human tissues. Both subtypes are widely distributed in the central nervous system and in the heart, blood vessels, and other tissues. VIP has a high affinity for both receptor subtypes. Binding of VIP to its receptors results in activation of adenylyl cyclase and formation of cAMP, which is responsible for the vasodilation and many other effects of the peptide. Other actions may be mediated by inositol trisphosphate synthesis and calcium mobilization. 

After dopamine was identified as a neurotransmitter in 1959, it was shown that its effects on electrical activity in central synapses and on production of the second messenger cAMP by adenylyl cyclase could be blocked by antipsychotic drugs such as chlorpromazine, haloperidol, and thiothixene. This evidence led to the conclusion in the early 1960s that these drugs should be considered dopamine-receptor antagonists and was responsible for the dopamine hypothesis of schizophrenia described earlier in this chapter. The antipsychotic action is now thought to be produced (at least in part) by their ability to block dopamine in the mesolimbic and mesocortical systems. 

Many of the manifestations of thyroid hyperactivity resemble sympathetic nervous system overactivity (especially in the cardiovascular system), although catecholamine levels are not increased. Changes in catecholamine-stimulated adenylyl cyclase activity as measured by cAMP are found with changes in thyroid activity. Possible explanations include increased numbers of 13 receptors or enhanced amplification of the 13 receptor signal. Other clinical symptoms reminiscent of excessive epinephrine activity (and partially alleviated by adrenoceptor antagonists) include lid lag and retraction, tremor, excessive sweating, anxiety, and nervousness. The opposite constellation of effects is seen in hypothyroidism (Table 38-4). 

Upon activation all three (X2AR subtypes are coupled to their intracellular messenger systems via heterotrimeric G /0 proteins (Figure 2). Intracellular consequences of 0C2AR activation are reduced cAMP levels due to inhibition of adenylyl cyclase, opening of GIRK K+ channels, inhibition of neuronal Ca2+ channels, and... 

---