Molecular Structure and Physiological Functions of GABA_BReceptors

Abstract

GABAB receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABAB receptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABAB system. This led to the surprising discovery that GABAB receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABAB receptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABAB receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABAB receptors and the receptors for γ-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABAB receptor polymorphisms to epilepsy. Significantly, the cloning of GABAB receptors enabled identification of the first allosteric GABAB receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABAB receptors and discuss ongoing drug-discovery efforts.

Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

“…GABA B receptors are expressed extensively in the PAG 124 and are coupled to G i/o subunits, 127 AC is a downstream effector of GABA B receptors. 128 Elevated PKA activity increased GABA currents, causing depolarization and stimulation of GABAergic neurons in the PAG.…”

Loss of dendritic inhibition in the hippocampus after repeated early-life hyperthermic seizures in rats

“…Kindling (Asprodini et al, 1992;Poon et al, 2006) and status epilepticus models resulted in a decrease in GABA B R function (Mangan and Lothman, 1996;Chandler et al, 2003;Straessle et al, 2003), which was suggested to contribute to seizure susceptibility. Additionally, GABA B R1 knockout mice developed spontaneous seizures (Bettler et al, 2004), and acute GABA B R blockade increased partial seizure susceptibility in animals (Leung et al, 2005).…”

Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABAB receptors in cortical neurons

“…Two main variants of GABA B1 that differ in their N-terminal domain are generated by alternative promoter usage (Steiger et al, 2004) and give rise to two GABA B receptor subtypes, GABA B1a /GABA B2 and GABA B1b /GABA B2 . They are abundantly expressed in all major brain structures and control excitability of neurons by mediating slow inhibitory neurotransmission (for a review see Bettler et al, 2004).…”