Inhibition of adenylyl cyclase

Desaubry L, Shoshani I, Johnson RA (1996) Inhibition of adenylyl cyclase by a family of newly synthesized adenine nucleoside 3 -polyphosphates. J Biol Chem 271 14028-14034... 

Activation of Mi, M3, and M5 mAChRs does not only lead to the generation of IP3 followed by the mobilization of intracellular Ca2+, but also results in the stimulation of phospholipase A2, phospholipase D, and various tyrosine kinases. Similarly, M2 and M4 receptor activation does not only mediate the inhibition of adenylyl cyclase, but also induces other biochemical responses including augmentation of phospholipase A2 activity. Moreover, the stimulation of different mAChR subtypes is also linked to the activation of different classes of mitogen-activated protein kinases (MAP kinases), resulting in specific effects on gene expression and cell growth or differentiation. 

Pertussis toxin is produced by the bacterium Bordetella pertussis. It covalently modifies G-proteins of the G/Go family (transfer of a ADP-ribose moiety of NAD onto G-protein a-subunits). ADP-ribosylated G-proteins are arrested in their inactive state and, as a consequence, functionally uncoupled from their respective effectors. Examples for pertussis toxin-sensitive cellular responses include the hormonal inhibition of adenylyl cyclases, stimulation ofK+ channels, inhibition of Ca2+ channels and stimulation ofthe cGMP-phosphodiesterase in retinal rods. 

Transduction mechanism Inhibition of adenylyl cyclase stimulation of tyrosine phosphatase activity stimulation of MAP kinase activity activation of ERK inhibition of Ca2+ channel activation stimulation of Na+/H+ exchanger stimulation of AM PA/kainate glutamate channels Inhibition of forskol in-stimulated adenylyl cyclase activation of phos-phoinositide metabolism stimulation of tyrosine phosphatase activity inhibition of Ca2+ channel activation activation of K+ channel inhibition of AM PA/ kainate glutamate channels inhibition of MAP kinase activity inhibition of ERK stimulation of SHP-1 and SHP-2 Inhibition of adenylyl cyclase stimulation of phosphoinositide metabolism stimulation of tyrosine phosphatase activation of K+ channel inhibi-tion/stimulation of MAP kinase activity induction of p53 and Bax Inhibition of adenylyl cyclase stimulation of MAP kinase stimulation of p38 activation of tyrosine phosphatase stimulation of K+ channels and phospholipase A2 Inhibition of adenylyl cyclase activation/ inhibition of phosphoinositide metabolism inhibition of Ca2+ influx activation of K+ channels inhibition of MAP kinase stimulation of tyrosine phosphatase... 

Figure 25-8. Control of adipose tissue lipolysis. (TSH, thyroid-stimulating hormone FFA, free fatty acids.) Note the cascade sequence of reactions affording amplification at each step. The lipolytic stimulus is "switched off" by removal of the stimulating hormone the action of lipase phosphatase the inhibition of the lipase and adenylyl cyclase by high concentrations of FFA the inhibition of adenylyl cyclase by adenosine and the removal of cAMP by the action of phosphodiesterase. ACTFI,TSFI, and glucagon may not activate adenylyl cyclase in vivo, since the concentration of each hormone required in vitro is much higher than is found in the circulation. Positive ( ) and negative ( ) regulatory effects are represented by broken lines and substrate flow by solid lines.

The multiplicity of G proteins coupled to opiate receptors may explain how different opiates can bind to the same receptor yet induce different cellular responses. For example, morphine binds to the cloned rat fi receptor expressed in HEK 293, CHO and COS-7 cells and inhibits cAMP accumulation [80-82]. Morphine can be continuously applied to the cells for up to 16 h, and the potency and magnitude of morphine inhibition of adenylyl cyclase does not diminish [80, 81]. In contrast, the opiate sufentanil can bind to the same cloned fi receptor in HEK 293 cells to inhibit cAMP accumulation. However, sufentanil s actions rapidly desensitize [83]. Since both compounds bind to the same receptor, and the fi receptor is the only receptor these drugs can interact with in these cells, the ability of these two full agonists to differentially regulate the fi receptor must be due to their abilities to affect separate adaptive processes in these cells. 

McKenzie FR, Milligan G. Delta-opioid-receptor-mediated inhibition of adenylyl cyclase is transduced specifically by the guanine-nucleotide-binding protein Gi2. Biochem J 1990 267 391-398... 

Muscarinic receptor activation causes inhibition of adenylyl cyclase, stimulation of phospholipase C and regulation of ion channels 203... 

Muscarinic receptor activation causes inhibition of adenylyl cyclase, stimulation of phospholipase C and regulation of ion channels. Many types of neuron and effector cell respond to muscarinic receptor stimulation. Despite the diversity of responses that ensue, the initial event that follows ligand binding to the muscarinic receptor is, in all cases, the interaction of the receptor with a G protein. Depending on the nature of the G protein and the available effectors, the receptor-G-protein interaction can initiate any of several early biochemical events. Common responses elicited by muscarinic receptor occupation are inhibition of adenylyl cyclase, stimulation of phos-phoinositide hydrolysis and regulation of potassium or other ion channels [47] (Fig. 11-10). The particular receptor subtypes eliciting those responses are discussed below. (See also Chs 20 and 21.)... 

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-HT receptor family comprises the 5-HT1Ar 5-HT1Bi 5-HT1Dr 5-ht1E and 5-ht1F receptors. The five receptor subtypes in the 5-HT, receptor family share 40-63% overall sequence homology. These 5-HT receptors couple preferentially to the inhibition of adenylyl cyclase via the Gi/0 family of G proteins (see Ch. 21). 

Inhibition of adenylyl cyclase opening of K+ channels Inhibition of adenylyl cyclase... 

However, in the dorsal raphe nucleus, 5-HT1A receptors are coupled to the opening of potassium channels but do not appear to be coupled to the inhibition of adenylyl cyclase. 

In contrast, pertussis toxin catalyzes the ADP-ribosyl-ation of a specific cysteine residue in Gai) G(m and Gal [1]. Only a subunits bound to their Py subunits can undergo this modification. Pertussis-toxin-mediated ADP-ribosylation inactivates these a subunits such that they cannot exchange GTP for GDP in response to receptor activation (Fig. 19-1B). By this mechanism, pertussis toxin blocks the ability of neurotransmitters to inhibit adenylyl cyclase or to influence the gating of K+ and Ca2+ channels in target neurons. However, since G is not a substrate for pertussis toxin, the toxin may not be able to block neurotransmitter-mediated inhibition of adenylyl cyclase in all cases. The Gq and Gn 16 types of G protein a subunit are not known to undergo ADP-ribosylation. 

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). 

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... 

---