Potentiation of TRPV4 signalling by histamine and serotonin: an important mechanism for visceral hypersensitivity

Background

Although evidence points to a role for histamine and serotonin in visceral hypersensitivity, activation of calcium channels such as transient receptor potential vanilloid 4 (TRPV4) also causes visceral hypersensitivity. We hypothesised that TRPV4 is important for the generation of hypersensitivity, mediating histamine- and serotonin-induced visceral hypersensitivity.

Methods

In response to histamine, serotonin and/or TRPV4 agonist (4αPDD), calcium signals and TRPV4 localisation studies were performed on dorsal root ganglia (DRG) neurons projecting from the colon. To evaluate visceral nociception, colorectal distension (CRD) was performed in mice treated with serotonin or histamine and with 4αPDD. Intrathecal injection of TRPV4 silencer RNA (SiRNA) or mismatch SiRNA was used to target TRPV4 expression.

Results

Pre-exposure of DRG neurons projecting from the colon, to histamine or serotonin, increased Ca²⁺ responses induced by 4αPDD by a protein kinase C (PKC), phospholipase Cβ (PLCβ), mitogen-activated protein kinase kinase (MAPKK) and phospholipase A₂ (PLA₂)-dependent mechanisms. Serotonin or histamine treatments enhanced TRPV4 expression at the plasma membrane by a MAPKK mechanism. Hypersensitivity induced by serotonin or histamine were both significantly inhibited by TRPV4 SiRNA intrathecal injection. Administration of sub-nociceptive doses of serotonin or histamine potentiated 4αPDD-induced hypersensitivity in response to CRD.

Conclusions

Serotonin and histamine sensitise TRPV4 response to 4αPDD both in vivo (increased visceral hypersensitivity) and in vitro, in sensory neurons, by a PKC, PLA₂, PLCβ and MAPKK-dependent mechanism. Serotonin and histamine caused a MAPKK-dependent increase in TRPV4 expression in colonic sensory neurons plasma membranes. Further, histamine- or serotonin-mediated visceral hypersensitivity depend on TRPV4 expression in sensory neurons. TRPV4 appears as a common mechanism to several known mediators of visceral hypersensitivity.