Role of GABA_B Receptors in Autonomic Control of Systemic Blood Pressure

Abstract

GABA_B receptors belong to family III G protein-coupled receptors (GPCRs) and are widely distributed in the peripheral and central nervous systems. The GABA_B receptor is one of the most important therapeutic targets in the treatment for spasticity. GABA_B agonists, such as baclofen, are used as muscle relaxants clinically and are effective for the treatment of anxiety, depression, epilepsy, and cognitive disorders (Caddick and Hosford, 1996, Dichter, 1997, Enna and Bowery, 1997). In addition, GABA_B receptors regulate neurotransmitter release and neuronal excitability in the brain regions involved in the autonomic nervous system. Recent studies have led to a better understanding of the role of GABA_B in the regulation of the autonomic nervous system, especially in disease conditions such as hypertension. Here, we provide an overview of the recent progress, a discussion of disparate and contradictory findings, and a description of theories used to explain various cardiovascular effects of GABA_B receptor drugs. Particular emphasis is placed on the role of GABA_B receptors in the neural plasticity of brain regions related to the control of sympathetic outflow in cardiovascular disorders.

Introduction

γ-Aminobutyric acid (GABA) is a ubiquitous inhibitory neurotransmitter and is widely distributed throughout the central nervous system (CNS). The responses to GABA are mediated by the activation of membrane receptors and by specific uptake mechanisms that control the spatial and temporal pattern of GABAergic transmission. GABA activates three pharmacologically distinct types of receptors: ionotropic GABA_A and GABA_C receptors and G protein-coupled GABA_B receptors (Table I) (Bowery, 1993, Bowery and Enna, 2000). The early component of GABA inhibition is mediated by GABA_A receptors (Macdonald & Olsen, 1994). These receptors belong to the ion channel superfamily and typically produce a rapid, chloride-mediated membrane hyperpolarization in response to GABA and GABA_A receptor agonists. The late component of inhibitory transmission, first identified in sympathetic neurons, is slower and not affected by GABA_A receptor antagonists (Hill and Bowery, 1981, Mott and Lewis, 1994). Three decades ago, the receptors responsible for the late component of inhibition were named GABA_B (Hill & Bowery, 1981). Upon being activated, GABA_B receptors mediate hyperpolarization of postsynaptic membranes and inhibition of presynaptic neurotransmitter release (Misgeld et al., 1995). Also, GABA_B receptors play important roles in regulating long-term potentiation (Davies et al., 1991), neuroblast migration (Behar et al., 1995), and rhythmic activity in the hippocampus (Scanziani, 2000). GABA_B receptors are family III G protein-coupled receptors (GPCRs) and activation of these receptors results in GDP/GTP exchange in the associated G proteins and diffusion of Gα and Gβγ subunits for the activation of a wide variety of intracellular effector systems (Kubo and Tateyama, 2005, Mott and Lewis, 1994). Activation of GABA_B receptors leads to either an increase or a decrease in the intracellular level of cyclic AMP, depending upon the types of adenylyl cyclases in the cell (Bowery & Enna, 2000).

Numerous GABA_B receptor subunit isoforms have been identified. Initial studies indicated that fully functional GABA_B receptors must be composed of a GABA_B1 and a GABA_B2 protein (Bowery and Enna, 2000, Chronwall et al., 2001, Jones et al., 1998, Kaupmann et al., 1998). The cDNA for GABA_B1 has been cloned (Kaupmann et al., 1997, Dichter, 1997, Enna and Bowery, 1997) and this gene produces two predominant amino-terminal splice variants: GABA_B1a and GABA_B1b. Expression of either GABA_B1a or GABA_B1b alone does not possess a fully functional GABA_B receptor. In addition, the GABA_B2 cDNA was cloned and characterized (Jones et al., 1998, Kaupmann et al., 1998, Kuner et al., 1999, White et al., 1998). Coexpression of GABA_B1 and GABA_B2 proteins represents the similar form of heteromeric dimers of the wild-type GABA_B receptors (Jones et al., 1998, Kaupmann et al., 1998, Kuner et al., 1999, White et al., 1998). The dimers result from a physical interaction between the GABA_B1 and GABA_B2 proteins within their carboxyl-terminal cytoplasmic tails (Kuner et al., 1999). GABA_B2 receptors act as chaperons for the trafficking and insertion of GABA_B1 proteins into the cell membrane (White et al., 1998). However, it is essential that GABA_B2 attach to GABA_B1 after membrane insertion for the complete expression of GABA_B receptor function. However, more recent findings suggest that GABA_B1 alone or GABA_B1 homodimers can display some activity as well (Gassmann et al., 2004).

In the past decades, increasing evidence demonstrated that GABA_B receptors play important roles in the regulation of the autonomic nervous system including sympathetic output, cardiovascular reflexes (e.g., baro- and chemoreflexes), and energy balance (Amano and Kubo, 1993, Avanzino et al., 1994, Lemus et al., 2008, Persson, 1981, Suzuki et al., 1999, Sved and Sved, 1989, Sved and Sved, 1990). Furthermore, alterations of GABA_B receptor expression and function in autonomic centers have been reported in cardiovascular disease conditions such as hypertension (Durgam et al., 1999, Li and Pan, 2006, Li and Pan, 2007a, Li et al., 2008a, Sved and Sved, 1989, Sved and Tsukamoto, 1992, Takenaka et al., 1996, Tsukamoto and Sved, 1993, Zhang and Mifflin, 2010b). However, it is not clear that the plasticity of GABA_B receptors in hypertension is a cause of elevated sympathetic activity or an adaptive change to high level of blood pressure. This chapter summarizes the latest findings about the role of GABA_B receptors in the regulation of cardiovascular function.