PubMed- Butyrate-induced colonic hypersensitivity is mediated by mitogen-activated protein kinase activation in rat dorsal root ganglia.
Posted 27 July 2012 - 07:52 AM
Butyrate-induced colonic hypersensitivity is mediated by mitogen-activated protein kinase activation in rat dorsal root ganglia.
Gut. 2012 Jul 24;
Authors: Xu D, Wu X, Grabauskas G, Owyang C
ObjectiveIncreased faecal butyrate levels have been reported in irritable bowel syndrome. Rectal instillation of sodium butyrate (NaB) increases visceral sensitivity in rats by an unknown mechanism. We seek to examine the signal transduction pathways responsible for the enhanced neuronal excitability in the dorsal root ganglion (DRG) following NaB enemas and demonstrate that this is responsible for the colonic hypersensitivity reported in this animal model.DesignColorectal distention (CRD) studies were performed in rats treated with NaB rectal instillation with/without intrathecal or intravenous administration of mitogen-activated protein (MAP) kinase kinase inhibitor U0126. Western blot analysis and immunocytochemistry studies elucidated intracellular signalling pathways that modulate I(A). Patch-clamp recordings were performed on isolated DRG neurons treated with NaB, with/without U0126.ResultsVisceromotor responses (VMR) were markedly enhanced in NaB-treated rats. Western blot analysis of DRG neurons from NaB-treated rats showed a 2.2-fold increase in phosphorylated ERK1/2 (pEKR1/2) and 1.9-fold increase in phosphorylated voltage-gated potassium channel subunit 4.2 (pKv4.2). Intrathecal or intravenous administration of U0126 reduced VMR to CRD in NaB-treated rats and prevented increases in pERK1/2 and pKv4.2. Patch-clamp recordings of isolated DRG neurons showed that NaB caused a reduction in I(A) to 48.9%±1.4% of control and an increase in neuronal excitability, accompanied by a twofold increase in pERK1/2 and pKv4.2. Concurrent U0126 administration prevented these changes.ConclusionsVisceral hypersensitivity induced by colonic NaB treatment is mediated by activation of the MAP kinase-ERK1/2 pathway, which phosphorylates Kv4.2. This results in a reduction in I(A) and an enhancement of DRG neuronal excitability.
PMID: 22833396 [PubMed - as supplied by publisher]View the full article