The non-selective cation channel Transient Receptor Potential Ankyrin 1 (TRPA1) is known to be a key contributor to both somatosensation and pain. Recent studies have implicated TRPA1 in additional physiologic functions, and have also suggested that TRPA1 is expressed in non-neuronal tissues. Thus, it has become necessary to resolve the importance of TRPA1 expressed in primary sensory neurons, particularly since prior research has largely utilized global knockout animals and chemical TRPA1 antagonists. We therefore sought to isolate the physiological relevance of TRPA1 specifically within sensory neurons. To accomplish this, we utilized Advillin-Cre mice, in which the promoter for Advillin is used to drive expression of Cre recombinase specifically within sensory neurons. These Advillin-Cre mice were crossed with Trpa1 fl/fl mice to generated sensory neuron-specific Trpa1 knockout mice. Here, we show that tissue-specific deletion of TRPA1 from sensory neurons produced strong deficits in behavioral sensitivity to mechanical stimulation, while sensitivity to cold and heat stimuli remained intact. The mechanical sensory deficit was incomplete compared to the mechanosensory impairment of TRPA1 global knockout mice, in line with the incomplete (∼80%) elimination of TRPA1 from sensory neurons in the tissue-specific knockout mice. Equivalent findings were observed in tissue-specific knockout animals originating from two independently-generated Advillin-Cre lines. As such, our results show that sensory neuron TRPA1 is required for mechanical, but not cold, responsiveness in non-injured skin.
Significance Statement To date, most studies on the function of TRPA1 have used either global knockout animals or antagonists, which do not allow for tissue specificity in their interpretation. Given that TRPA1 is expressed in multiple cell types, cell-type specific targeting is necessary to elucidate the mechanisms through which TRPA1 facilitates mechanosensation and other physiologic functions. Our results show that deletion of TRPA1 from sensory neurons is sufficient to induce significant impairment in baseline mechanical sensitivity, but does not impact behavioral cold aversion. Beyond the important clarification that the expression of TRPA1 specifically within sensory neurons is necessary for mechanosensation in mouse, sensory neuron-specific TRPA1 knockout animals will be beneficial in future studies focused on isolating additional tissue-specific functions of TRPA1.
Authors report no conflict of interest.
This research was supported by funding through NIH grants NS040538 and NS070711 to C.L.S., and by NS087716 to K.J.Z. Funding for K.Y.K. was through the Duncan and Nancy MacMillan Faculty Development Chair Endowment Fund, Busch Biomedical Research Grant, Rutgers Faculty Development Grant, and R01 DC015000-01. Partial support provided by the Research and Education Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin. Further, K.J.Z. is a member of the MCW-MSTP which is partially supported by a T32 grant from NIGMS, GM080202.