Research Article: Sensitization of TRPA1 by Protein Kinase A

Date Published: January 11, 2017

Publisher: Public Library of Science

Author(s): Jannis E. Meents, Michael J. M. Fischer, Peter A. McNaughton, Alexander G. Obukhov.


The TRPA1 ion channel is expressed in nociceptive (pain-sensitive) somatosensory neurons and is activated by a wide variety of chemical irritants, such as acrolein in smoke or isothiocyanates in mustard. Here, we investigate the enhancement of TRPA1 function caused by inflammatory mediators, which is thought to be important in lung conditions such as asthma and COPD. Protein kinase A is an important kinase acting downstream of inflammatory mediators to cause sensitization of TRPA1. By using site-directed mutagenesis, patch-clamp electrophysiology and calcium imaging we identify four amino acid residues, S86, S317, S428, and S972, as the principal targets of PKA-mediated phosphorylation and sensitization of TRPA1.

Partial Text

The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is expressed in nociceptive (pain-sensitive) somatosensory neurons, and activation of the channel triggers a sensation of stinging pain [1–4]. TRPA1 responds to a wide range of chemically diverse agonists, including natural products such as allyl-isothiocyanate (AITC, present in mustard oil and wasabi) and carvacrol (present in oregano) [2,5,6]; environmental toxins, such as acrolein (present in cigarette smoke) and nicotine [7,8]; common pharmaceuticals, such as lidocaine and propofol [9,10]; as well as a range of endogenous mediators [11,12] and protons [13]. TRPA1 has also been proposed to be activated by noxious cold [4,14,15] but this remains controversial [2,16]. Both intracellular and extracellular calcium can activate TRPA1 and potentiate its response to several agonists, followed by long lasting inactivation of the channel [2,16–18]. In contrast, under calcium-free conditions TRPA1 is strongly sensitized by prolonged application of agonists, through a slow shift of the channel’s voltage-dependence to more negative membrane voltages, and it has been proposed that this agonist-induced sensitization is important for the pain caused by prolonged exposure to irritants and allergens which activate TRPA1 [19].

The gating of TRPV1 is rapidly and potently enhanced when PKA or PKC are activated by a variety of inflammatory mediators, and also when TrkA is activated by the binding of NGF (reviewed in [22]). In preliminary studies we examined the ability of each of these signalling pathways to potentiate TRPA1. In agreement with other authors we found little short-term potentiation of TRPA1 by either PKC or by the NGF/TrkA pathway (S1 and S2 Figs). Activation of PKA, on the other hand, has a strong potentiating effect on gating of TRPA1, and so we focussed on elucidating the mechanism of action of this kinase.




0 0 vote
Article Rating
Notify of
Inline Feedbacks
View all comments