Cross-talking between 5-HT3 and GABAA receptors in cultured myenteric neurons.

ABSTRACT

We recorded whole-cell ion currents induced by gamma-aminobutyric acid (I(GABA)) and serotonin (I(5-HT)) to investigate and characterize putative interactions between GABA(A) and 5-HT(3) receptors in myenteric neurons from the guinea pig small intestine. I(GABA) and I(5-HT) were inhibited by bicuculline and ondansetron, respectively. Currents induced by the simultaneous application of both, GABA and 5-HT (I(GABA+5-HT)) were significantly lower than the sum of I(GABA) and I(5-HT), indicating the existence of a current occlusion. Such an occlusion was observed when GABA(A) and 5-HT(3) receptors are virtually saturated. Kinetics, and pharmacological properties of I(GABA+5-HT) indicate that they are mediated by activation of both, GABA(A) and 5-HT(3) channels. GABA did not alter I(5-HT) in neurons without GABA(A) channels, in the presence of bicuculline (a GABA(A) receptor antagonist) or at the reversal potential for I(GABA). Similarly, 5-HT did not modify I(GABA) in neurons in which 5-HT(3) channels were absent, after inhibiting 5-HT(3) channels with ondansetron (a 5-HT(3) receptor antagonist) or at the reversal potential for I(5-HT). Current occlusion was observed as soon as GABA(A) and 5-HT(3) channels were being activated, in the absence of Ca(2+), at low temperature (11 degrees C), and after adding staurosporine (a protein kinase inhibitor) to the pipette solution. Our proposal is that GABA(A) and 5-HT(3) channels are organized in clusters and within these, both channels can cross-inhibit each other, likely by allosteric interactions between these proteins.