GABAb receptor

GABA is the predominant inhibitory neurotransmitter in the CNS. Baclofen acts centrally as an agonist at the GABAb receptor, which increases inhibition of nerves. 3-Aminopropylphosphinic acid (3-APPi) has been shown experimentally to act as an antitussive at peripheral nerves and preclinical evidence suggests that baclofen indeed has antitussive actions clinically [3]. 

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. 

Currently, baclofen is the only clinically used GAB Ab receptor agonist. It is used as a muscle relaxant for treatment of spasticity in spinal injury and multiple sclerosis. The cloning of GABAb receptors has renewed the interest in the search for more selective diugs and novel therapeutic indications. 

GABA is the most prominent inhibitory neurotransmitter in the mammalian nervous system and acts via GABA receptors. Activation of GABAb receptors by GABA released from local spinal interneurons (Fig. 1) negatively modulates nociceptive transmission in the spinal cord. Agonists at GABAb receptors... 

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. 

GABAa Receptors GABAb Receptors GABAergic System Gaddum Galanin... 

The enantiomerically pure 3-arylglutaric ester are precursors for the synthesis of (—)-paroxetine [10], a selective serotonin reuptake inhibitor used in the treatment of depression, obsessive compulsive disorder, and panic, and (i )-Baclofen [11], a GABAb receptor agonist, which is used cHnically in the treatment of spasticity (Chart 5.1). 

Amino acid receptors Monoamine receptors Lipid receptors Purine receptors Neuropeptide receptors Peptide hormone receptors Chemokine receptors Glycoprotein receptors Protease receptors Metabotropic glutamate and GABAb receptors Adrenoceptors, dopamine and 5-HT receptors, muscarinic and histamine receptors Prostaglandin, thromboxane and PAF receptors Adenosine and ATP (P2Y) receptors Neuropeptide Y, opiate, cholecystokinin VIP, etc. Angiotensin, bradykinin, glucagon, calcitonin, parathyroid, etc. Interleukin-8 TSH, LH/FSH, chorionic gonadotropin, etc. Thrombin... 

The GABAb receptors were the first G-protein-coupled receptors to be observed to form functional heterodimers (Bowery and Enna 2000) where two G-protein molecules come together to act as a dimer to enhance their combined response. A similar effect has recently also been described for dopamine and somatostatin receptors (Rocheville et al. 2000) and it is likely that this may occur with other G-protein-coupled receptors. The significance of this in terms of the pharmacology of the receptors is unclear, or indeed whether dimerisation affects mechanisms such as desensitisation. 

Bowery, NG (1993) GABAb receptor pharmacology. Ann. Rev. Pharmacol. Toxicol. 33 109-147. 

Dutar, P and Nicoll, RA (1988) A physiological role for GABAb receptors in the central nervous system. Nature 332 156-158. 

Kaupmann, K, Huggel, K, Held, J, Flor, PJ, Bischoff, S, Mickel, SJ, McMaster, G, Angst, C, Bittiger, H, Froestl, W and Bettler, B (1997) Expression cloning of GABAb receptors uncovers similarity to metabotropic glutamate receptors. Nature 386 239-246. 

Kaupmann, K, Malitschek, B, Schuler, V, Held, J, Froestl, W, Beck, P, Mosbacher, J, Bischoff, S, Kulik, A, Shigemoto, R, Karschin, A and Bettler, B (1998) GABAB-receptor subtypes assemble into functional heteromeric complexes. Nature 396 683-687. 

The reason for this disappointing response is uncertain but may be due to desensitisation of the GABAa receptors, or the actual inhibition of GABA inhibitory neurons through somatic autoreceptors which could disrupt the precise timing of physiological inhibition. Activation of the GABAb receptor with baclofen has no... 

In the spinal cord GABA can also activate the G-protein-linked GABAb receptor, also found pre- and postsynaptically. Baclofen modulation of nociceptive transmission is seen under inflammatory conditions in animals but in humans the drug appears to lack any analgesic effect. 

Kuner R, Kohr G, Grunewald S, Eisenhardt G, Bach A, Komau HC. Role of heteromer formation in GABAB receptor function. Science 1999 283(5398) 74-77. 

The GABAb receptor is not a single 7TM receptor but rather a heterodimer formed by two 7TM receptors from family C. The GABAb-R1 receptor, which was initially cloned, binds the ligand GABA, but when expressed alone it is to a large extent retained in the endoplasmic reticulum,... 

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