An mRNA Encoding a Putative GABA‐Gated Chloride Channel Is Expressed in the Human Cardiac Conduction System

Abstract

GABA-gated chloride channels are the main inhibitory neurotransmitter receptors in the CNS. Conserved domains among members of previously described GABAA receptor subunits were used to design degenerate sense and antisense oligonucleotides. A PCR product from this amplification was used to isolate a full-length cDNA. The predicted protein has many of the features shared by other members ofthe ligand-gated ion channel family. This channel subunit has significant amino acid identity (25-40%) with members of GABAA and GABAC receptor subunits and thus may represent a new subfamily of the GABA receptor channel. Although we cannot rule out that this clone encodes a receptor for an unidentified ligand, it was termed GABA x. This gene is mainly expressed in placenta and in heart; however, placenta appears to express only an unspliced mRNA. In situ hybridization reveals that the GABA~subunit mANA is present in the electrical conduction system of the human heart. Our results suggest that novel GABA receptors expressed outside of the CNS may regulate cardiac function.

Analysis of the Set of GABAA Receptor Genes in the Human Genome

“…The mRNAs of variants 2 and 3 have indeed been found by Wilke et al (33) in several peripheral tissues. The full-length human ⑀ expression is high in heart and lung and is also present in brain (33,54,55), and the same is true for the rat (36); in human heart it is confined to the electrical conduction system and is located throughout it (54), suggesting a specialized non-neuronal role there. The other variants lack the signal peptide and also (for forms 2 and 3) lack a significant region of the extracellular N-terminal domain, but roles for those in combination with other (full-length) subunits or in regulation of GABA receptor trafficking remain possibilities.…”

“…We have confirmed a total of 9 ⑀ subunit exons in the genome, all nine being coding exons. Four expressed ⑀ variants can be found, the first being the full-length functional transcript (33,(53)(54)(55). In variant 2, exons 1-3 are spliced out, with protein translation then starting at an alternative Met.…”

Heterogeneity of GABAA Receptors: Revived Interest in the Development of Subtype-selective Drugs

“…The ε subunit originally has been cloned from human tissue [42,77,78]. An unusually high level of divergence from their human homologs was detected in the rat tissue in one report [79] that could not be confirmed in another study [80].…”

Pharmacological Properties of GABAAReceptors in Rat Hypothalamic Neurons Expressing the ϵ-Subunit

“…Properties of native GABA A Rs depend on their subunit combination; for example, they can be allosterically modulated by many drugs in wide clinical use, such as benzodiazepines and anesthetics (Fritschy and Brunig, 2003). A gene encoding the ⑀-subunit of the GABA A R was first reported by three independent groups in 1997 (Davies et al, 1997;Garret et al, 1997;Whiting et al, 1997). Expression of the ⑀-subunit gene is restricted to a few brain regions: it was found in primate hippocampal dentate gyrus and hypothalamus (Whiting et al, 1997), as well as in rat hypothalamus and aminergic nuclei (Moragues et al, 2000(Moragues et al, , 2002.…”