Cross‐talking between 5‐HT₃ and GABA_A 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.

Interactions between the anxiogenic effects of CB1 gene disruption and 5-HT3 neurotransmission

“…Moreover, in one study both the 5-HT 3 antagonist zacopride and the agonist mCPBG produced anxiogenic effects (Andrews and File, 1992). Such inconsistencies were explained by 5-HT 3 effects on serotonin release (Blier and Bouchard, 1993;Bagdy et al, 1998) and interactions with noradrenaline, glycine, and GABA neurotransmission (Mongeau et al, 1994;Maksay, 1996;Chesnoy-Marchais et al, 2000;Miranda-Morales et al, 2007). Our findings suggest that the highly inconsistent effects of 5-HT 3 ligands on anxiety are at least partly explained by the interaction between 5-HT 3 -mediated serotonergic neurotransmission and cannabinoid signaling.…”

GABAA Receptors: Post-Synaptic Co-Localization and Cross-Talk with Other Receptors

“…However, a recent study for the first time described a cross-talk between 5-HT 3 Rs and GABA A Rs in myenteric neurons using whole-cell recordings (Miranda-Morales et al, 2007), by providing evidence for current occlusion on simultaneous activation of these two receptors. The cross-talk as observed at saturating concentration of agonists for both receptors occurred immediately after the application of the two agonists, possibly suggesting that the two receptors are located very close to each other.…”

Involvement of 5‐HT3 and 5‐HT4 receptors in colonic motor patterns in rats

“…9 A number of studies suggest that alterations in 5-HT signaling may contribute to colonic motor disorders but inconsistencies exist among these investigations. 3,11 Unraveling the exact modes of action of 5-HT in regulating gut motor activity is complicated because of the multiple sources of 5-HT, the multiple receptor subtypes, pre-and postsynaptic actions, 3,12 potentially constitutively active receptors and the many targets of 5-HT. 13,14 This is particularly true for whole organ studies; but such studies remain essential since most motor patterns are not revealed in simpler preparations such as muscle strips.…”