Gi/o-coupled receptors

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. 

Measurement of the regulation of cAMP-dependent reporter gene expression, inhibition of constitutive mobilization of intracellular Ca2+, and enhancement of neurotransmitter release have also been used to detect inverse agonism in other Gi/o coupled receptor systems [see 8 for review] ... 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

The pertussis toxin sensitivity and, hence, Gi/o coupling of 5-HTib autoreceptors in rat striatum (Section4.1) and of the 5-HTib heteroreceptors inhibiting dopamine release in rat striatum (Section4.4) also holds true for the 5-HTib heteroreceptors inhibiting acetylcholine release in rat hippocampus (Sarhan and Fillion 1999). Presynaptic HT4 receptors increase cAMP levels which in turn, by stimulating protein kinase A, may inhibit K+ channels to enhance transmitter release (Eglen et al. 1995). 

Honda, S., Sasaki, Y., Ohsawa, K., Imai, Y., Nakamura, Y., Inoue, K., and Kohsaka, S. (2001). Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J. Neurosci. 21, 1975-1982. 

In many cell types, D2 receptor stimulation has an effect on enzymes metabolizing membrane lipids. We have mentioned above that in mesenchyme-derived cells and in striatal neurons, D2 agonists stimulate the activity of PLCp by mobilizing Gpy complex, and produce an inositol triphosphate-dependent Ca2+ release from intracellular stores (Ghahremani et al., 1999). In CHO cells stably transfected with D2 receptors, D2 agonists potently enhance the release of arachidonic acid when intracellular Ca2+ levels are already enhanced. This effect was observed following stimulation of various Gi/o-coupled... 

Opioids such as codeine, morphine and dihydrocodone are aU good antitussives primarily via their action at central p-opioid-receptors (Kamei 1996). It is not known, however, whether this occurs within the cough circuitry of the nTS, even though it is recognized that this location is rich in this receptor (Monteillet-Agius et al. 1998). These receptors are Gi/o-coupled and mediate presynaptic inhibition of neurotransmitter release (Emmerson and Miller 1999). Recently, both... 

GABAb receptors mediate the slow and prolonged physiological effects of the inhibitory neurotransmitter GABA. Functional GABAb receptors are comprised of two subunits, GABAbR1 and GABAbR2. Both subunits are G-protein-coupled receptors, which couple to the Gi/o family and are densely expressed at spinal nociceptive synapses. 

The 5-HTx receptor class comprises five receptors (5-HT1a, 5-HT1b, 5-HTiD, 5-ht1E> and 5-HT1F) which, in humans, share 40-63% overall sequence identity and couple somewhat preferentially to Gi/o to inhibit cAMP formation (see Tables 1-3). The 5-htiE receptors are given a lower case appellation to denote that... 

The GABAB-receptors, the muscarinic M2- and IVU-receptors for acetylcholine, the dopamine D2-, D3-and D4-receptors, the a2-adrenoceptors for noradrenaline, the 5-HTiA F-receptors for serotonin, and the opioid p-, 8- and K-receptors couple to G proteins of the Gi/o family and thereby lower [1] the cytoplasmic level of the second messenger cyclic AMP and [2] the open probability ofN- andP/Q-type Ca2+ channels (Table 1). The muscarinic Mr, M3- and M5-receptors for acetylcholine and the ai-adrenoceptors for noradrenaline couple to G proteins of the Gq/11 family and thereby increase the cytoplasmic levels of the second messengers inositol trisphosphate and diacylglycerol (Table 1). The dopamine Dr and D5-receptors and the (3-adrenoceptors for noradrenaline, finally, couple to Gs and thereby increase the cytoplasmic level of cyclic AMP. 

The Di-like receptors (Di, D5) couple predominantly to Gs and thus can stimulate adenylyl cyclase, yielding cAMP. The D2-like receptors (D2, D3, D4) couple to Gi/o proteins and may inhibit adenylyl cyclase or modulate many other different signalling molecules and pathways. D3 receptors may also couple to Gs (Obadiah et al. 1999 Ilani et al. 2002). 

Apart from its role as a major mediator of inflammation and allergic reactions and as physiological regulator of gastric acid secretion, histamine is also a neurotransmitter in the CNS. Central histaminergic cell bodies are located in the posterior hypothalamus and project diffusely to almost all brain regions and to the spinal cord. There are four types of histamine receptors, all G-protein-coupled, Hi, H2, H3 and H4. Hi receptors couple to Gq/11 proteins. H2 receptors couple to Gs. H3 and H4 receptors couple to Gi/o. 

HT interacts with a large diversity of G-protein-coupled receptors, namely the 5-HTi,2,4,5,6 and 7 families, and in addition with a ligand-gated cationic channel, 5-HT3. The diversity has been explained by the fact that serotonin is one of the oldest neurotransmitters in evolution. The 5-HTi receptor family (5-HTia,ib,id,ie andiF) couples mainly to Gi/o. 5-1 I I oa, 5-HT2B and 5-HT2C receptors couple to Gq/11. 5-HT4, 5-HT6, and 5-HT7 receptors couple to Gs. The 5-HT5A receptor couples principally to Gi/o. The 5-HTsb receptor seems to occur only in rodents, and no transduction mechanism has been identified. 

D2-like receptors couple mainly to Gi/o proteins, as mentioned above. However, there is no direct evidence to support this coupling for the release-modulating autoreceptors. Moreover, the subsequent intracellular signal transduction has never been studied directly in axon terminals. Mouse AtT-20 pituitary cells, which release acetylcholine and adrenocorticotropic hormone, have been used as a model for axon terminals. When expressed in these cells, D3 receptors mediated inhibition of P/Q-type calcium channels and activation of G protein-coupled inward rectifier potassium channels (Kuzhikandathil et al. 1998 Kuzhikandathil and Oxford 1999). Both would explain the autoreceptor-mediated inhibition of dopamine exocytosis. 

Single cell reverse transcription - polymerase chain reaction detected D2 and D5 but not D3/4 and little Di receptor mRNA in rat striatal cholinergic intemeurons. The D2 receptors coupled to Gi/o and reduced somatic N-type Ca2+ currents (Yan et al. 1997), thus providing a cellular mechanism for the reduction of acetylcholine release by D2 receptors located on cholinergic terminals. 

The results of Mizuno et al. (2007) make it likely that modulation of Ca2+ currents underlies the various modulations of GABA release. This view is supported by other studies for both D2-like inhibition (Pisani et al. 2000 Momiyama and Koga 2001) and Di-like facilitation (Arias-Montano et al. 2007). The D2-like inhibitory receptors presumably couple to Gi/o (Momiyama and Koga 2001), whereas the Di-like facilitatory receptors presumably couple to Gs, activation of adenylyl cyclase and activation of protein kinase A (Arias-Montano et al. 2007). The riddle of the exceptional cases of inhibition through Di-like receptors remains. For example, in rat prefrontal cortex Di-like receptors presynaptically inhibited GABAergic transmission, an effect blocked by an inhibitor of protein kinase A (Gonzalez-Islas and Hablitz 2001) - the same enzyme involved in facilitation through Di-like receptors... 

Arias-Montano et al. 2007). The occasional facilitation by presynaptic D3 receptors (Mizuno et al. 2007) may be due to the fact that this subtype can couple to Gs in addition to Gi/o (see Introduction). 

Presynaptic H3 receptors also are uniform in their signal transduction. They couple to Gi/o proteins and decrease the depolarization-induced release of neurotransmitters by inhibiting multiple calcium channels (e.g., Arrang et al. 1985 Schlicker et al. 1994 Endou et al. 1994 Brown and Haas 1999 see Stark et al. 2004). For comparison, the signal transduction of soma-dendritic H3 autoreceptors in histamin-ergic neurons also involves a pertussis toxin-sensitive G-protein with subsequent inhibition of N- and P-type Ca2+ channels (Takeshita et al. 1998). The few exceptions to this signal transduction pathway are discussed in the corresponding subsections below (see Sections 3.1, 3.3, and 3.9). 

Cox SL, Schelb V, Trendelenburg AU et al (2000) Enhancement of noradrenaline release by angiotensin II and bradykinin in mouse atria evidence for cross talk between Gq/11 protein- and Gi/o protein-coupled receptors. Br J Pharmacol 129 1095-1102 Cunha RA, Milusheva E, Vizi ES et al (1994a) Excitatory and inhibitory effects of Ai and A2a adenosine receptor activation on the electrically evoked [3H] acetylcholine release from different areas of the rat hippocampus. J Neurochem 63 207-14 Cunha RA, Ribeiro JA, Sebastiao AM (1994b) Purinergic modulation of the evoked release of [3 H] acetylcholine from the hippocampus and cerebral cortex of the rat role of the ectonucleotidases. Eur J Neurosci 6 33 42... 

NIH-3T3 cells. Those effects were blocked by pertussis toxin, supporting a role for Gi/o proteins (174). The relevance of the coupling to PLC is unclear because the transfected cells used in this study expressed very high levels of receptors (4.4 pmol/mg of protein). 

Got subunits of the Gi/o type of G proteins can be ADP-ribosylated in the presence of pertussis toxin at Cys351, four amino acids from the C-terminus. Petussis toxin sensitivity is the major method of identifying a role for Gai/o proteins in GPCR-mediated signaling. This treatment prevents receptor-mediated G-protein activation and thus exchange of GTP for GDP and so blocks signaling by Ga and G(3y. There are numerous examples of the use of this technique to identify coupling of the delta opioid receptor [e.g., 2,3,41,42,73,77]. One Ga protein in this class, Gaz, lacks the Cys residue that is the site for pertussis toxin action and so is insensitive to pertussis toxin treatment [see 17 for review]. 

Possible coupling of Dl-type receptors with Gi/o and Gq protein... 

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