摘要：

Molecular Structure and Physiological Functions of GAB[A.sub.B] Receptors. Physiol Rev 84: 835-867, 2004; 10.1152/ physrev.00036.2003.--GAB[A.sub.B] 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 GAB[A.sub.B] 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 GAB[A.sub.B] system. This led to the surprising discovery that GAB[A.sub.B] receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G proteincoupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GAB[A.sub.B] 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 GAB[A.sub.B] receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GAB[A.sub.B] receptors and the receptors for [gamma]-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GAB[A.sub.B] receptor polymorphisms to epilepsy. Significantly, the cloning of GAB[A.sub.B] receptors enabled identification of the first allosteric GAB[A.sub.B] receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GAB[A.sub.B] receptors and discuss ongoing drug-discovery efforts. I. INTRODUCTION GABA is the major inhibitory neurotransmitter in the central nervous system (CNS) and as such plays a key role in modulating neuronal activity. GABA mediates its action via distinct receptor systems, the ionotropic GAB[A.sub.A] and metabotropic GAB[A.sub.B] receptors. Unlike GAB[A.sub.A] receptors that form ion channels, GAB[A.sub.B] receptors address second messenger systems through the binding and activation of guanine nucleotide-binding proteins (G proteins; for other recent reviews on GAB[A.sub.B] receptors, see Refs. 45, 55). Dysfunction of GABA-mediated synaptic transmission in the CNS is believed to underlie various nervous system disorders. For example, hypoactivity of the GABA system was linked to epilepsy, spasticity, anxiety, stress, sleep disorders, depression, addiction, and pain. On the contrary, hyperactivity of the GABAergic system was associated with schizophrenia (20). GABA research, because of its medical relevance, has always attracted a great deal of attention in academia and industry. Over the years pharmaceutical companies successfully exploited the GABA system and introduced a number of drugs to the market. However, despite considerable drug-discovery efforts, baclofen ([beta]-chlorophenyl-GABA, Lioresal) currently remains the only available GAB[A.sub.B] medication. Baclofen, a lipophilic derivative of GABA, was synthesized in 1962 in an attempt to enhance the blood-brain barrier penetrability of the endogenous neurotransmitter. Baclofen was introduced to the market in 1972 and is used to treat spasticity and skeletal muscle rigidity in patients with spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, and cerebral palsy (44). GAB[A.sub.B] agonists showed promising therapeutic effects in a whole range of other indications, but their side effects, including sedation, tolerance, and muscle relaxation, prevented further development (see sect....

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