3-Iodothyronamine increases transient receptor potential melastatin channel 8 (TRPM8) activity in immortalized human corneal epithelial cells

3-Iodothyronamine (3T(1)AM) is an endogenous thyroid hormone metabolite that interacts with the human trace amine-associated receptor 1 (hTAAR1), a G-protein-coupled receptor, to induce numerous physiological responses including dose-dependent body temperature lowering in rodents. 3T(1)AM also directly activates cold sensitive transient receptor potential melastatin 8 (TRPM8) channels in human conjunctival epithelial cells (HCjEC) at constant temperature as well as reducing rises in IL-6 release induced by transient receptor potential vanilloid 1 (TRPV1) activation by capsaicin (CAP). Here, we describe that 3T(1)AM-induced TRPM8 activation suppresses through crosstalk TRPV1 activation in immortalized human corneal epithelial cells (HCEC). RT-PCR and immunofluorescent staining identified TRPM8 gene and protein expression. Increases in Ca2+ influx induced by the TRPM8 agonists either 3T(1)AM (0.1-10 mu M), menthol (500 mu M), icilin (15-60 mu M) or temperature lowering (either <17 degrees C or >17 degrees C) were all blocked by 10-20 mu M BCTC, a mixed TRPV1/TRPM8 antagonist. BCTC blocked 3T(1)AM-induced recombinant TRPM8 activation of Ca2+ transients in an osteosarcoma heterologous expression system. The effects of BCTC in HCEC were attributable to selective TRPM8 inhibition since whole-cell patch clamp currents underlying Ca2+ rises induced by 20 mu M CAP were BCTC insensitive. On the other hand, Ca2+ transients induced by activating TRPV1 with either CAP or a hyperosmolar medium were suppressed during exposure to either 1 mu M 3T(1)AM or 15 mu M icilin. All of these modulatory effects on intracellular Ca2+ regulation induced by the aforementioned agents were attributable to changes in underlying inward and outward current. Taken together, TRPM8 activation by 3T(1)AM markedly attenuates and even eliminates hyperosmolar and CAP induced TRPV1 activation through crosstalk. (C) 2015 Elsevier Inc All rights reserved.