The transient receptor potential melastatin type 8 (TRPM8) receptor channel is expressed in primary afferent neurons where it is the main transducer of innocuous cold temperatures and also in a variety of tumors, where it is involved in progression and metastasis. Modulation of this channel by intracellular signaling pathways has therefore important clinical implications. We investigated the modulation of recombinant and natively expressed TRPM8 by the Src kinase, which is known to be involved in cancer pathophysiology and inflammation. Human TRPM8 expressed in HEK293T cells is constitutively tyrosine phosphorylated by Src which is expressed either heterologously or endogenously. Src action on TRPM8 potentiates its activity, as treatment with PP2, a selective Src kinase inhibitor, reduces both TRPM8 tyrosine phosphorylation and cold‐induced channel activation. RNA interference directed against the Src kinase diminished the extent of PP2‐induced functional downregulation of TRPM8, confirming that PP2 acts mainly through Src inhibition. Finally, the effect of PP2 on TRPM8 cold activation was reproduced in cultured rat dorsal root ganglion neurons, and this action was antagonized by the protein tyrosine phosphatase inhibitor pervanadate, confirming that TRPM8 activity is sensitive to the cellular balance between tyrosine kinases and phosphatases. This positive modulation of TRPM8 by Src kinase may be relevant for inflammatory pain and cancer signaling.
Psoralen is a naturally occurring furanocoumarin, found in the seeds of Psoralea corylifolia, and also in figs, celery, parsley and citrus fruits, which has been used to treat a number of skin conditions since the antiquity (Pathak & Fitzpatrick, 1992). In modern medicine, psoralen-derived compounds, such as 8-methoxypsoralen (8-MOP) and 5-methoxypsoralen (5-MOP), are used in combination with UVA light (320-400 nm) exposure (PUVA therapy) to treat severe psoriasis, eczema, vitiligo, cutaneous T-cell lymphoma, mycosis fungoides and other conditions (Lapolla, Yentzer,
Transient Receptor Potential (TRP) channels are a superfamily of polymodal, non-selective receptors, expressed in the nervous system and several other tissues, where they play many physiological or pathological roles. TRP channels are sensitive to a diverse range of stimuli, such as temperature, osmolarity, oxidative stress, external compounds and intracellular signaling molecules. The activity of TRP channels can be modulated by protein phosphorylation, including tyrosine phosphorylation. In this review, we present the studies carried out so far regarding the modulation of TRP channels by tyrosine phosphorylation.
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