Odontoblast TRPC5 channels signal cold pain in teeth

Abstract

Teeth are composed of many tissues, covered by an inflexible and obdurate enamel. Unlike most other tissues, teeth become extremely cold sensitive when inflamed. The mechanisms of this cold sensation are not understood. Here, we clarify the molecular and cellular components of the dental cold sensing system and show that sensory transduction of cold stimuli in teeth requires odontoblasts. TRPC5 is a cold sensor in healthy teeth and, with TRPA1, is sufficient for cold sensing. The odontoblast appears as the direct site of TRPC5 cold transduction and provides a mechanism for prolonged cold sensing via TRPC5’s relative sensitivity to intracellular calcium and lack of desensitization. Our data provide concrete functional evidence that equipping odontoblasts with the cold-sensor TRPC5 expands traditional odontoblast functions and renders it a previously unknown integral cellular component of the dental cold sensing system.

Odontoblasts are cold sensory cells in teeth

“…In our study, we describe that these highly specialized cells function also as cold sensory cells and thereby constitute the important transduction component in the tooth's damage sensing system [1]. This is much in contrast to the skin, where pain from damaging pressure or noxious temperatures is generated at the level of the primary afferent nociceptors.…”

“…In the mouse, the skin-saphenous nerve preparation served to decipher the molecular detection mechanisms of skin cold nociceptors and thermoreceptors [3]. Thus, in our study, we developed a new ex vivo model of the dental sensing system in the mouse [1]. This preparation allows to register propagated action potentials from the inferior alveolar nerve which innervates the mouse molars and incisor.…”

A role for TRPC5 in cold sensing, finally

“…Cold sensing in teeth is even less well understood than in skin, likely reflecting the fact that the anatomical situation is highly challenging to the experimenter, with the site of cold transduction rendered rather inaccessible by the tough shield of enamel and dentin. To circumvent this problem, Bernal et al developed a preparation to record from single nerve fibers in the nerve that innervates the teeth of the lower jaw [ 1 ]. Working with mice, this preparation enabled the genetic dissection of the responses of dental sensory neurons to cold stimuli.…”

“…Working with mice, this preparation enabled the genetic dissection of the responses of dental sensory neurons to cold stimuli. Interestingly, but maybe not unexpectedly, Bernal et al, in a recent study published in Science Advances [ 1 ], found that deleting TRPM8, TRPA1, and TRPC5 channels individually did not eliminate the cold response from dental sensory neurons. Surprisingly, however, they found that eliminating TRPC5 channels had the largest effect roughly halving the number of cold-sensitive fibers.…”

“…While much work remains to be done to fill in the details (including the direct demonstration of functional TRPC5 channels in odontoblasts), the work of Bernal et al strongly favors a model in which odontoblasts are sensory cells excited by cold stimuli which signal their activation to neurons close by, possibly via the release of ATP [ 8 ]. The exciting findings of Bernal et al therefore add significantly to the emerging concept that somatosensory neurons are not the only agents in stimulus detection, but work in concert with, or even secondary to other, non-neuronal cells, such as odontoblasts [ 1 , 8 ], Merkel cells [ 5 ], or keratinocytes [ 9 ].…”