Neurotransmitter mechanisms mediating low-glucose signalling in cocultures and fresh tissue slices of rat carotid body
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The mammalian carotid body (CB) is a polymodal chemosensor which can detect low blood glucose (hypoglycaemia), leading to increased afferent discharge and activation of counter-regulatory autonomic pathways. The underlying neurotransmitter mechanisms are unknown and controversy surrounds whether the action of low glucose is direct or indirect. To address this, we used a coculture model containing functional chemosensory units of rat CB receptor (type I) cell clusters and afferent petrosal neurones (PN). During perforated-patch, whole-cell recordings, low glucose (0-2 mM) stimulated sensory discharge in cocultured PN. When the background P(O2) was lowered to levels typical of arterial blood (approximately 90 mmHg), robust PN chemoexcitation could be induced by physiological hypoglycaemia (3.3-4 mM glucose). These sensory responses were reversibly inhibited by a combination of purinergic (suramin, 50 microM) and nicotinic (mecamylamine, 1 microM) receptor blockers, suggesting that transmission depended on corelease of ATP and ACh. Hypoglycaemic responses were additive with those evoked by hypoxia or hypercapnia; further, they could be potentiated by the GABAB receptor blocker (CGP 55845) and inhibited by 5-HT2A receptor blockers (ketanserin or ritanserin). During paired simultaneous recordings from a PN and a type I cell in an adjacent cluster, the afferent PN response coincided with type I cell depolarization, which was associated with a decrease in input resistance. In fresh tissue slices of rat CB, low glucose stimulated ATP secretion as determined by the luciferin-luciferase assay; this secretion was cadmium sensitive, potentiated by CGP 55845, and inhibited by ketanserin. Taken together these data indicate that CB receptors act as direct glucosensors, and that processing of hypoglycaemia utilizes similar neurotransmitter and neuromodulatory mechanisms as hypoxia.
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