Gi-coupled receptors

Weber, M., Ferrer, M., Zheng, W., Inglese, J., Strulovici, B., and Kunapuli, P., A 1536-well cAMP assay for Gs- and Gi-coupled receptors using enzyme fragmentation complementation, Assay Drug Dev. Technol., 2, 39, 2004. 

Redfem C, Coward P, Degtyarev M, et al. 1999. Conditional expression and signaling of specifically designed Gi-coupled receptor in transgenic mice. Nat Biotechnol 17 165-169. 

Redfern C, Degtyarev M, et al. 2000. Conditional expression of a Gi-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy. Proc Natl Acad Sci USA 97 4826-4831. 

KOCH WJ, HAWES BE, ALLEN LF, LEFKOWITZ RJ (1994) Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras . Proceedings ofthe National Academy ofSciences ofthe United States of America, 91,12706-12710. 

Van Brocklyn, J., Letterle, C., Snyder, P., and Prior, T. Sphingosine-l-phosphate stimulates human glioma cell proliferation through Gi-coupled receptors role of ERK MAP kinase and phosphatidylinositol 3-kinase beta. Cancer Lett, 181, 2002, 195-204. 

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. 

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. 

Similar to endogenous opioids, opiates like morphine and other synthetic opioids activate G-protein-coupled receptors which couple to G-proteins of the Gi/0 family. 

The 3 isozymes are activated by G protein-coupled receptors through two different mechanisms [2]. The first involves activated a-subunits of the Gq family of heterotrimeric G proteins (Gq, Gn, Gi4, G15/16). These subunits activate the (31, (33 and (34 PLC isozymes through direct interaction with a sequence in the C terminus. The domain on the Gqa-subunit that interacts with the (3 isozymes is located on a surface a-helix that is adjacent to the Switch III region, which undergoes a marked conformational change during activation. The second mechanism of G protein activation of PLC 3 isozymes involves (3y-subunits released from Gi/0 G proteins by their pertussis toxin-sensitive activation by certain receptors. The 3y-subunits activate the 32 and 33 PLC isozymes by interacting with a sequence between the conserved X and Y domains. 

LPA binds and activates specific G-protein-coupled receptors found in many cells (review Moolenaar et al., 1997). The LPA receptor can transmit the signal to G,-, Gj-or Gi2-proteins. If Gq is involved, an InsPs and Ca signal is produced in the cell, whereas signal conduction via Gi- or Gu-proteins flows into the Ras pathway or activates the Rho proteins, respectively (see Chapter 9). 

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. 

Histamine is not only a mediator of several (patho)physiological actions, but also functions as a neurotransmitter, both centrally as peripherally [1, 2]. Feedback mechanisms are crucial to neurotransmission and the presynaptic histamine H3 receptor not only plays a key role in regulating histamine release but also regulates the release of other neurotransmitters (for further details see chapter 2 and 3). Because inhibitory effects on histamine H3 receptor-mediated stimuli by G protein toxins (both cholera and pertussin toxin) have been reported, it is most likely that the histamine H3 receptor also belongs to the superfamily of G protein-coupled receptors [3,4], i.e. coupled to a G protein of the Gi/0 class [5]. The reader is referred to chapter 6 for more details. 

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