Cyclic adenosine monophosphate receptor

Nissley, P., Anderson, W. B., Gallo, M., Pastan, I., Perlman, R. L. The binding of cyclic adenosine monophosphate receptor to deoxyribonucleic acid. J. biol. Chem. 247, 4264-4269 (1972). 

Serotoninergic System. Figure 1 Graphical representation of the current classification of 5-hydroxytryptamine (5-HT) receptors. Receptor subtypes represented by shaded boxes and lowercase designate receptors that have not been demonstrated to definitively function in native systems. Abbreviations 3-5r cyclic adenosine monophosphate (cAMP) phospholipase C (PLC) negative (-ve) positive (+ve)... 

A sequence stretch 300 base pairs upstream of the transcriptional start site suffices for most of the transcriptional regulation of the IL-6 gene (Fig. 1). Within this sequence stretch several transcription factors find their specific recognition sites. In 5 to 3 direction, AP-1, CREB, C/EBP 3/NF-IL6, SP-1 and NF-kB can bind to the promoter followed by TATA and its TATA binding protein TBP. Most enhancer factors become active in response to one or several different stimuli and the active factors can trigger transcription individually or in concert. For example, AP-1 is active upon cellular stress, or upon stimuli that tell cells to proliferate CREB becomes also active if cells experience growth signals, but also upon elevation of intracellular levels of cyclic adenosine monophosphate (cAMP), which occurs upon stimulation if so called hormone-activated G protein-coupled receptors. 

The effect of receptor stimulation is thus to catalyze a reaction cycle. This leads to considerable amplification of the initial signal. For example, in the process of visual excitation, the photoisomerization of one rhodopsin molecule leads to the activation of approximately 500 to 1000 transdudn (Gt) molecules, each of which in turn catalyzes the hydrolysis of many hundreds of cyclic guanosine monophosphate (cGMP) molecules by phosphodiesterase. Amplification in the adenylate cyclase cascade is less but still substantial each ligand-bound P-adrenoceptor activates approximately 10 to 20 Gs molecules, each of which in turn catalyzes the production of hundreds of cyclic adenosine monophosphate (cAMP) molecules by adenylate cyclase. 

The most common second messenger activated by protein/peptide hormones and catecholamines is cyclic adenosine monophosphate (cAMP). The pathway by which cAMP is formed and alters cellular function is illustrated in Figure 10.1. The process begins when the hormone binds to its receptor. These receptors are quite large and span the plasma membrane. On the cytoplasmic surface of the membrane, the receptor is associated with a G protein that serves as the transducer molecule. In other words, the G protein acts as an intermediary between the receptor and the second messengers that will alter cellular activity. These proteins are referred to as G proteins because they bind with guanosine nucleotides. In an unstimulated cell, the inactive G protein binds guanosine diphosphate (GDP). When the hormone... 

Dl-iike receptors activate the Gs transduction pathway, stimulating the production of adenylyl cyclase, which increases the formation of cyclic adenosine monophosphate (cAMP) and ultimately increases the activity of cAMP-dependent protein kinase (PKA). PKA activates DARPP-32 (dopamine and cyclic adenosine 3, 5 -monophosphate-regulated phosphoprotein, 32 kDa) via phosphorylation, permitting phospho-DARPP-32 to then inhibit protein phosphatase-1 (PP-1). The downstream effect of decreased PP-1 activity is an increase in the phosphorylation states of assorted downstream effector proteins regulating neurotransmitter... 

Antidepressant treatment has, in recent studies, been shown to upregulate the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) cascade and expression of BDNF [59]. This upregulation of CREB and BDNF raises the possibility that antidepressant treatment could oppose the cell death pathway, possibly via increased expression of the oncogene Bcl-2. Studies are necessary to determine if antidepressant treatment increases Bcl-2 expression. Increased expression of Bcl-2 in brain and cultured cells, and inhibition of apoptosis of cultured cerebellar granule neurons have been reported with lithium treatment [57]. Mice lacking the BDNF TrkB receptor fail to show behavioral and neurogenic responses to antidepressants. 

The short-acting / -agonists (Table 80-1) are the most effective broncho-dilators available. /J2-Adrenergic receptor stimulation activates adenyl cyclase, which produces an increase in intracellular cyclic adenosine monophosphate. This results in smooth muscle relaxation, mast cell membrane stabilization, and skeletal muscle stimulation. 

Theophylline and aminophylline may produce bronchodilation by inhibition of phosphodiesterase (thereby increasing cyclic adenosine monophosphate levels), inhibition of calcium ion influx into smooth muscle, prostaglandin antagonism, stimulation of endogenous catecholamines, adenosine receptor antagonism, and inhibition of release of mediators from mast cells and leukocytes. 

Cimetidine increases cyclic adenosine monophosphate concentration in smooth muscle, causes muscle to relax Antiulcerant Histamine H2 receptor antagonist, reduces volume of gastric... 

Metabotropic receptors, in contrast, create their effects by activating an intracellular G protein. The metabotropic receptors are monomers with seven transmembrane domains. The activated G protein, in turn, may activate an ion channel from an intracellular site. Alternately, G proteins work by activation or inhibition of enzymes that produce intracellular messengers. For example, activation of adenylate cyclase increases production of cyclic adenosine monophosphate (cAMP). Other effector mechanisms include activation of phospholipases, diacylglycerol, creation of inositol phosphates, and production of arachidonic acid products. Ultimately, these cascades can result in protein phosphorylation. 

Fig. 6.4 In vitro effects of mutation on desensitization and internalization of the dopamine receptor. Shown here are effects of mutation on dose-dependent intracellular cyclic adenosine monophosphate (cAMP) accumulation (A and B) and binding curves (C and D) for artificial ligand (SCH 23390) using three constructs controls (wild type, A and C) and the Thr360Ala mutant (360, B and D). In the desensitization experiments, cells were preincubated with 10 oA/ dopamine (o) or vehicle ( ) for 20min, and increasing concentrations of dopamine (10 to 10 (iM) were added to assess cAMP accumulation. Note that loss of efficacy and potency seen in wild-type cells (A) disappeared with the Thr360Ala mutation (B). Conversely, internalization, assessed by decrease in SCH23390 binding (C) after pretreatment with lOpM dopamine (o, compared to vehicle ), was essentially unchanged by the Thr360Ala mutation (D)...

TTie second messenger, for example cyclic adenosine monophosphate (cAMP), then activates cAMP-dependent protein kinase which modulates the function of a broad range of membrane receptors, intracellular enzymes, ion channels and transcription factors. 

To date, five subtypes of these receptors have been cloned. However, initial studies relied on the pharmacological effects of the muscarinic antagonist pirenzepine which was shown to block the effect of several muscarinic agonists. These receptors were termed Mi receptors to distinguish them from those receptors for which pirenzepine had only a low affinity and therefore failed to block the pharmacological response. These were termed M2 receptors. More recently, M3, M4 and M5 receptors have been identified which, like the Mi and M2 receptors occur in the brain. Recent studies have shown that Mi and M3 are located posts)maptically in the brain whereas the M2 and M4 receptors occur pres)maptically where they act as inhibitory autoreceptors that inhibit the release of acetylcholine. The M2 and M4 receptors are coupled to the inhibitory Gi protein which reduces the formation of cyclic adenosine monophosphate (cyclic AMP) within the neuron. By contrast, the Mi, M3 and M5 receptors are coupled to the stimulatory Gs protein which stimulates the intracellular hydrolysis of the phosphoinositide messenger within the neuron (see Figure 2.8). 

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). 

Autonomic receptors further regulate calcium influx through the sarcolemma (Fig. 15.1). (3-Adrenergic stimulation results in the association of a catalytic subunit of a G protein coupled to the (3-receptor. This stimulates the enzyme adenylyl cyclase to convert ATP to cyclic adenosine monophosphate (cAMP). Increasing cAMP production results in a cAMP-dependent phosphorylation of the L-type calcium channel and a subsequent increase in the probability of the open state of the channel. This translates to an increase in transsarcolemmal calcium influx during phase 2 (the plateau phase) of the cardiac muscle action potential. The effects of transient increases in intracellular levels of cAMP are tightly con-... 

Several classes of drugs, notably the antipsychotics, discussed in Chapter 34, interfere with dopaminergic transmission. In general, dopamine appears to be an inhibitory neurotransmitter. Five dopamine receptors have been identified the most important and best studied are the Dj. and D2.receptor groups. The Dj receptor, which increases cyclic adenosine monophosphate (cAMP) by activation of adenylyl cyclase, is located primarily in the region of the putamen, nucleus accum-bens, and in the olfactory tubercle. The D2 receptor decreases cAMP, blocks certain calcium channels, and opens certain potassium channels. 

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 postsynaptic S-adrenoceptors (jS-ARs) belong to the rhodopsin/ S2 adrenergic receptor-like receptors that belong to one of three major subfamilies of the GPCRs [83]. The S-AR family is subdivided into at least three discrete subtypes, the ySr, )S2-AR [84], and the atypical jSa-AR [85,86]. Additionally, a putative subtype has been identified in cardiac tissue, classified as the P4-AR [87], The P-]- and S2-AR are Gs-protein coupled, thereby elevating the intracellular level of cyclic adenosine monophosphate (cAMP) and causing positive inotropic and chronotropic effects [88]. The P2-AR can also couple to the Grprotein. 

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