Recent advances have underscored cell-to-cell communication as an important component of the operation of taste buds with individual taste receptor cells (TRCs) communicating with oneanother by means of a number of neurotransmitters and neuropeptides, although functional roles are not yet understood. Here, we characterize the presence, distribution pattern, phenotype, and functional consequences of a previously undescribed inhibitory route within the taste bud mediated by the classic neurotransmitter GABA and its receptors. By using immunocytochemistry, subsets of TRCs within rat taste buds were identified as expressing GABA, and its synthetic enzyme glutamate decarboxylase (GAD). GAD expression was verified with Western blotting. Immunofluorescent studies revealed complex coexpression patterns of GAD with the TRC protein markers gustducin, neural cell adhesion molecule, protein gene product 9.5, and synaptosomal-associated protein of 25 kDa that collectively outline hardwired signaling pathways of GABAergic TRCs. RT-PCR and immunocytochemistry demonstrated that both GABA A and GABAB receptors are expressed in the taste bud. The later was observed in a subset TRCs paracrine to GAD-expressing TRCs. Physiological effects of GABA were examined by patch clamp recordings. GABA and the GABAA agonists muscimol and isoguvacine enhanced isolated chloride currents in a dose-dependent manner. Also, GABA and the GABAB agonist baclofen both elicited increases of the inwardly rectifying potassium currents that could be blocked by the GABAB receptor antagonist CGP 35348 and the G protein blocker GDP-S. Collectively, these data suggest that GABAergic TRCs are able to shape the final chemosensory output of the bud by means of processes of cell-to-cell modulation.gustation ͉ neuromodulation ͉ neurotransmitters ͉ transduction ͉ paracrine signaling R ecent studies of gustatory transduction (1, 2) have dramatically altered our understanding of how the taste bud operates. Early views of taste-bud function were based on anatomical studies and classified taste receptor cells (TRCs) into types I, II, or III. Type III cells are synaptically connected to afferent nerve fibers and were considered as ''true'' receptor cells, because they communicate directly with the central nervous system. Types I and II, differing in their opacity (dark or light, respectively) lack synapses, and were considered supportive cells. The discovery of the 7 transmembrane receptor families T1R and T2R and other downstream signaling molecules in type II cells changed the view that single TRCs operate in isolation but instead function collectively through cell-to-cell communication in producing the neural output (3, 4). The notion has lead to discussing transduction as early, or primary, events leading to activation of late, or secondary, events. Early events involve steps leading to the activation (i.e., depolarization) of an individual TRC. Tastant molecules interact with receptors of the T1R or T2R families in type II cells or with ion channels such as the trp...