Control of sensory neuron excitability by serotonin involves 5HT2C receptors and Ca2+-activated chloride channels

Abstract

Serotonin (5HT) is a constituent of the so-called “inflammatory soup” that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na+ channels or Kv7 K+ channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl− currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca2+-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs.

TMEM16A expression in cholinergic neurons of the medial habenula mediates anxiety‐related behaviors

“…E In the LDB task, the time spent in the light zone by CNO-treated ChAT(+)-cre::hM4D(Gi) mice was significantly decreased compared to that by the PBS-treated control mice. This is consistent with our previous finding that TMEM16A contributes to depolarization of the dorsal root ganglia [15,16,31]. F In the PA task, the entry latency of CNO-treated mice was significantly decreased compared to that of the CTL group.…”

“…They exert diverse roles, including epithelial secretion of electrolytes and smooth muscle cell contraction [14]. In the peripheral nervous system in particular, CaCCs have been ascribed to setting the membrane potential and membrane depolarization via chloride efflux [15,16]. Since the identification of TMEM16A (also called anoctamin-1) as a CaCC [17][18][19], TMEM16A and TMEM16B are accepted as CaCCs.…”

Morphological and functional diversity of first-order somatosensory neurons

“…The reversal potential for Cl − is variable from cell to cell, so the opening of channels selective for Cl − can lead to either reduced excitation or depolarization. In DRG neurons, the calcium-activated chloride channels promote depolarization (Mayer 1985) and their activation by inflammatory mediators induces repetitive firing (Salzer et al 2016).…”

Mouse Anaphylactic Hypotension Is Characterized by Initial Baroreflex Independent Renal Sympathoinhibition Followed by Sustained Renal Sympathoexcitation

“…TRPV1 is stimulated by heat, low pH and many compounds (Caterina et al, 1997 ; Tominaga et al, 1998 ). Recently, anaphylactic mediators such as histamine (Kim et al, 2004 ; Shim et al, 2007 ), serotonin (Salzer et al, 2016 ), platelet-activating factor (Marotta et al, 2009 ), and prostaglandins (Moriyama et al, 2005 ) sensitize and activate TRPV1. On the other hand, TRPV1 is reported to be involved in regulations of hemorrhagic shock via the baroreceptors (Akabori et al, 2007 ) and vagal afferents (Zhang et al, 2017 ).…”