β-Alanine as a small molecule neurotransmitter

Abstract

This review discusses the role of β-alanine as a neurotransmitter. β-Alanine is structurally intermediate between α-amino acid (glycine, glutamate) and γ-amino acid (GABA) neurotransmitters. In general, β-alanine satisfies a number of the prerequisite classical criteria for being a neurotransmitter: β-alanine occurs naturally in the CNS, is released by electrical stimulation through a Ca²⁺ dependent process, has binding sites, and inhibits neuronal excitability. β-Alanine has 5 recognized receptor sites: glycine co-agonist site on the NMDA complex (strychnine-insensitive); glycine receptor site (strychnine sensitive); GABA-A receptor; GABA-C receptor; and blockade of GAT protein-mediated glial GABA uptake. Although β-alanine binding has been identified throughout the hippocampus, limbic structures, and neocortex, unique β-alaninergic neurons with no GABAergic properties remain unidentified, and it is impossible to discriminate between β-alaninergic and GABAergic properties in the CNS. Nevertheless, a variety of data suggest that β-alanine should be considered as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. These realizations open the door for a more comprehensive evaluation of β-alanine's neurochemistry and for its exploitation as a platform for drug design.

Introduction

Since neurotransmitters are central players in information propagation within the central and peripheral nervous systems, they are crucial molecular platforms in normal brain function and in the pharmacological manipulation of abnormal brain function. Historically, the most important neurotransmitters have been small molecules (acetylcholine, norepinephrine, dopamine), which have provided fundamental insights into normal neurochemistry and into the molecular basis of disease processes.

Amongst small molecule neurotransmitters, amino acid neurotransmitters are major players. α-Amino acids (e.g. the excitatory glutamate and inhibitory glycine neurotransmitters) and γ-amino acids (e.g. the inhibitory γ-aminobutyric acid [GABA] transmitter) contribute to the most fundamental processes of brain (arousal, sleep, consciousness) and to the pathogenesis of the disorders (epilepsy, stroke, dementia) that affect these processes. Structurally, amino acid neurotransmitters are extremely simple molecules possessing an anionic carboxylate (–COO⁻) on one end and a cationic ammonium (–NH₃⁺) on the other end. In α-amino acids, the carboxylate and ammonium termini are separated by a 2.5 Å one carbon bridge; in γ-amino acids the carboxylate and ammonium termini are separate by a 5.1 Å three carbon bridge.

On the basis of structural arguments, it is reasonable that a structurally intermediate β-amino acid, with a carboxylate-ammonium separation formed by a 3.8 Å two-carbon bridge, would be geometrically juxtaposed between α- and γ-amino acid neurotransmitters and could be a member of a sequential analogue series of information transmitting neurochemicals (see Fig. 1). Moreover, such a structurally intermediate (yet conformationally flexible) amino acid might afford additional opportunities to fine tune the careful balance between excitatory and inhibitory processes within the brain.

Structurally, β-alanine is the simplest possible β-amino acid, having no substituents on its central two-carbon bridge (Scriver et al., 1966). β-Alanine is one of only a few naturally occurring β-amino acids endogenous to humans and mammals (with taurine being the most studied). Despite not being used in the synthesis of any protein or enzyme, β-alanine does exhibit physiological significance. β-Alanine occurs within the human central nervous system (CNS) and some authors have suggested that it functions probably as a neuromodulator (DeFeudis and Martin del Rio, 1977) or perhaps even a neurotransmitter (Sandberg and Jacobson, 1981). In non-neural tissues, it occurs in multiple forms: as a free amino acid, as part of coenzyme A's pantothenic acid moiety, as a product of l-aspartate and uracil metabolism, and as a by-product of aspartic acid decarboxylation by gut microbes (Hayaishi et al., 1961). Within muscle, β-alanine exists as a component of the dipeptide carnosine (β-alanyl-histidine).

The purpose of this review is to analyze β-alanine neurochemistry and to ascertain whether β-alanine has the properties necessary to be a neurotransmitter (and not “just” a neuromodulator). To approach this analysis, the review is structured in three parts: Part A reviews the known biochemistry of β-alanine; Part B determines if these biochemical data are sufficient to classify β-alanine as a neurotransmitter; Part C examines the implications of classifying β-alanine as a neurotransmitter.