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Signal Transduction by GABAB Receptor Heterodimers Kenneth A

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Signal Transduction by GABAB Receptor Heterodimers Kenneth A Signal Transduction by GABAB Receptor Heterodimers Kenneth A. Jones, Ph.D., Joseph A. Tamm, Ph.D., Douglas A. Craig, Ph.D. Wen-Jeng Yao, B.A., and Rosa Panico, B.S. GABAB receptors are G-protein-coupled receptors that the native GABAB receptor as a heterodimer composed of mediate inhibition throughout the central and peripheral GABABR1 and GABABR2 proteins. New data from nervous systems. A single cloned receptor, GABABR1, mutagenesis experiments are presented that point to amino which has at least three alternatively spliced forms, appears acid residues on GABABR1 critical for ligand activation of to account for the vast majority of binding sites in the brain the heterodimer. The possible role of GABABR2 in signal for high-affinity antagonists. In heterologous expression transduction is also discussed. The interdependent nature of systems GABABR1 is poorly expressed on the plasma the two subunits for receptor function makes the GABAB membrane and largely fails to couple to ion channels. A receptor a useful model to explore the larger significance of second gene, GABABR2, which exhibits moderately low GPCR dimerization for G-protein activation. homology to GABABR1, permits surface expression of [Neuropsychopharmacology 23:S41–S49, 2000] ϩ GABABR1 and the appearance of baclofen-sensitive K and © 2000 American College of Neuropsychopharmacology. Caϩϩ currents. We review the data that supports a model of Published by Elsevier Science Inc. KEY WORDS: Gamma-aminobutyric acid; GABA(B) mitter release by GABA is thought to occur by suppres- receptor; Dimerization; Signal transduction sion of any of a number of identified high-threshold Caϩϩ channels (Harayama et al. 1998; Lambert and Wil- Gamma-aminobutyric acid (GABA) is an abundant son 1996; Mintz and Bean 1993; Dolphin and Scott neurotransmitter that mediates inhibition throughout 1987). The physiological importance of GABA recep- the nervous system via both ligand-gated channels B tors has been widely appreciated in humans through (GABA and GABA receptors) and G-protein-coupled A C the use of baclofen (Bowery et al. 1980), a selective ago- receptors (GABA receptor). GABA receptors have B B nist at GABA receptors that is used clinically for the both pre- and postsynaptic actions (Bowery 1993; Price B treatment of muscle spasticity and trigeminal neuralgia. et al. 1984). Postsynaptic inhibition of neuronal firing is The widespread distribution of GABAB receptors in mediated primarily by the coupling of GABAB recep- ϩ both central and peripheral nervous systems reveals tors to the activation of inwardly rectifying K channels their importance in a variety of physiological processes. (GIRKs) (North 1989; Gahwiler and Brown 1985; An- There is now a substantial repertoire of ligands, having drade et al. 1986). Presynaptic inhibition of neurotrans- agonist or antagonist properties, that display high affinity and selectivity for GABAB receptors (Froestl and Mickel 1997). Although these chemical tools have been useful for From the Synaptic Pharmaceutical Corporation, Paramus, NJ. studying the neurophysiology and molecular biology of Address correspondence to: Dr. Kenneth Jones, Dept. of Molecu- GABAB receptors, they have failed for the most part to lar Biology, Synaptic Pharmaceutical Corp., 215 College Rd., Para- permit the identification of pharmacological subtypes. For mus, NJ 07652. Tel.: (201) 261-1331 Ext. 735; Fax: (201) 261-0623; E-mail: [email protected] example, using semi-intact tissue preparations it is possi- Received April 6, 2000; accepted May 1, 2000. ble to record robust pre- and postsynaptic responses to ba- NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. S4 © 2000 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/00/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(00)00145-7 S42 K.A. Jones et al. NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. S4 clofen and high-affinity antagonists block these with transcripts were highly convergent throughout the brain roughly equal potency (Bon and Galvan 1996; Pozza et al. (Jones et al. 1998), suggesting that the two receptors 1999; Seabrook et al. 1990). Although measurements of were co-expressed in the same cellular regions. Double neurotransmitter release have permitted some groups to labeling of mRNAs and receptor proteins at cellular res- report selective antagonism (Fassio et al. 1994; Bonanno et olution provided proof that co-expression occurs in al. 1996, 1997; Teoh et al. 1996; but see also Baumann et al. multiple cell types, including cerebellar Purkinje cells, 1990), there is no general consensus about pharmacologi- hippocampal and cerebral cortical neurons, and the cally defined receptor subtypes (Bowery 1997). This is per- vast majority of neuronal somata within dorsal root haps surprising for a receptor system that is both wide- ganglia (Jones et al. 1998; Kaupmann et al. 1998a; Dur- spread and otherwise well characterized. kin et al. 1999). We reasoned that fully functional The identification of a gene encoding GABAB recep- GABAB receptors might somehow require the expres- tors proved to be at least as challenging as the pharma- sion of both GABABR1 and GABABR2. cological search for subtypes. Several groups attempted to expression clone a receptor using Xenopus oocytes (Uezono et al. 1998), or to biochemically characterize a CO-EXPRESSION STUDIES protein from brain, affinity purified using a monoclonal antibody (Nakayasu et al. 1993). The cloning break- Co-expression of GABABR1 and GABABR2 in Xenopus oo- through came with the development of the photo affin- cytes and mammalian cells leads to the development of ity radioligand, CGP71872. Using this as a marker, large amplitude GABA- and baclofen-sensitive GIRK cur- Kaupmann and co-workers (Kaupmann et al. 1997) rents (Jones et al. 1998; Kaupmann et al. 1998a; Kuner et al. identified a clone, GABABR1, predicted to encode a 1999; White et al. 1998; Ng et al. 1999). These currents are heptahelical protein composed of 844 amino acids. This rarely seen in cells expressing either gene alone (Kaup- clone shares many features of other members of the me- mann et al. 1998a, 1998b). Co-expression also permits ro- tabotropic glutamate and Caϩϩ-sensing receptor family bust inhibition of adenylyl cyclase (Kuner et al. 1999; Ng et including a large extracellular, N-terminal domain hav- al. 1999) as well as stimulation of GTP␥S binding in cell ing homology to bacterial amino acid binding proteins, membranes (White et al. 1998). The pharmacology of ago- such as LIVBP (O’Hara et al. 1993). When expressed nists at the GABABR1/R2 combination (Jones et al. 1998; heterologously in cell lines, the antagonist pharmacol- Brauner-Osborne and Krogsgaard-Larsen 1999; Lingen- ogy of the cloned receptor was shown to be very similar hoehl et al. 1999) is comparable to that reported for native to that of native receptors. In contrast, the apparent af- receptors (Bon and Galvan 1996; Seabrook et al. 1990). An- finity of agonist ligands was about 100-fold less than tagonist affinity estimates for saclofen, CGP54626 and expected from studies of brain membranes. When chal- CGP55845 (Jones et al. 1998; Brauner-Osborne and Krogs- lenged with an agonist, GABABR1 also did not appear gaard-Larsen 1999) are similar to values reported in previ- to be able to stimulate the expected cellular responses, ous electrophysiological studies using brain tissue (Bon such as Kϩ channel activation or robust inhibition of the and Galvan 1996; Seabrook et al. 1990), as well as to those accumulation of cAMP, which suggested that a neces- obtained by measuring displacement of radioligand from sary component of signal transduction was missing. cells expressing GABABR1 alone (Kaupmann et al. 1997). The publication of GABABR1 set off a search by Just as striking as the appearance of functional cellu- many groups for other genes having a related sequence. lar responses is the shift in affinity for agonists. The co- A query of public databases using the GABABR1 se- expression of GABABR2 with GABABR1 now results in quence led to the identification of a second, homolo- an apparent shift (10–30-fold) to a higher affinity state gous protein, GABABR2 (Jones et al. 1998; Kaupmann et for the agonists GABA and baclofen (Kaupmann et al. al. 1998a; Kuner et al. 1999; White et al. 1998; Martin et 1998a; White et al. 1998). This observation led to the al. 1999; Ng et al. 1999). Like GABABR1, GABABBR2 speculation that the two GABAB gene products might was found to contain a region homologous to LIVBP closely associate with one another (Kaupmann et al. within the large N-terminal extracellular domain. 1998a). Additional evidence came from epitope tagging Several groups have shown that when expressed in experiments that showed a high coincidence in the in- either oocytes or mammalian cells GABABR2 fails to tracellular distribution of the two proteins when ex- produce the anticipated cellular responses to GABA pressed heterologously (Jones et al. 1998). (Jones et al. 1998; Kaupmann et al. 1998a; White et al. 1998; but see also Kuner et al. 1999; Martin et al. 1999). This deficit in coupling was especially surprising consid- PHYSICAL ASSOCIATION BETWEEN GABABR1 ering the lack of function activity of GABABR1. Hinting AND GABABR2 at a resolution of the functional expression problem was the spatial distribution of the mRNAs for both GABABR1 Using immunoprecipitation methods, several groups and GABABR2. The in situ localization patterns of both demonstrated that GABABR1 and GABABR2 specifically NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. S4 Signal Transduction by GABAB Receptor Heterodimers S43 associate in a protein complex, probably as heterodimers transmembrane alpha helices are also critical for dimer (Jones et al. 1998; Kaupmann et al. 1998a; Kuner et al. formation or stabilization (Gouldson and Reynolds 1997; 1999; White et al. 1998). Furthermore, the heterodimers Hebert et al. 1996; Maggio et al. 1996; George et al. 1998). are concentrated on the plasma membrane, which suggests that the dimer is likely to be important for early events in signal transduction including ligand binding and G-protein CONSEQUENCES OF HETERODIMERIZATION activation (Jones et al.
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