258-LB: Vitamin D Directly Regulates TRPV1 Channel Activity and May Play an Important Role in the Autoimmune Disease of Type 1 Diabetes

Abstract

The autoimmune disease of type 1 diabetes (T1D) results in the immune destruction of β-cells. Recent studies suggest supplementation of vitamin D along can significantly improve patients’ β-cell function and glycemic control possibly by dampening naïve T-cell activation. However, the underlying cellular mechanism for this effect has not been elucidated completely, especially as naïve T-cells possess absent or very low VDR expression. Therefore, the effects of Vitamin D on naïve T-cells may involve a VDR-independent pathway. Interestingly, TRPV1 channel activation is necessary for naïve T-cell activation. Our initial calcium imaging and electrophysiological data show that Vitamin D (25OHD) can partially activate TRPV1. 25OHD can inhibit capsaicin induced TRPV1 activity. We propose that vitamin D is a partial agonist of TRPV1, through direct binding to TRPV1 and modulating naïve T-cell activation. Furthermore, our flow cytometry studies confirm both 25OHD and 1,25OHD significantly reduce TNFα/INFγ and IL2/IL4 production of mouse CD4+ naïve T-cells after 24 hours activation. Our results support the concept that naïve T-cell activation can be dampened by vitamin D in a VDR-independent manner, via an as yet undescribed mechanism involving the modulation of TRPV1 activity. Moreover, in silico and point-muatgenic experiments indicate 25-OHD binds to the same region as known TRPV1 agonist and antagonists. These novel findings provide evidence of an additional pathway for the action of Vitamin D action and advance our knowledge of the underlying cellular mechanism by which vitamin D may beneficially regulate naive T-cell activation in autoimmune disease such as T1D. Disclosure W. Long: Research Support; Self; JDRF. M. Fatehi: None. S. Soni: None. R. Panigrahi: None. R.G. Kelly: None. K. Philippaert: None. A.J. Barr: None. M. Held: None. Y. Yu: None. S.A. Campbell: None. K. Ondrusova: None. T. Baldwin: None. J. Lemieux: None. P.E. Light: None. Funding JDRF

Vitamin D and Its Potential Interplay With Pain Signaling Pathways

“…Therefore, for example, we and others have shown that a mutation in sodium channel Nav1.7 results in a complete loss of pain sensation (29,76) or in extreme pain phenotypes (77,78). Vitamin D, which is synthesized in the skin is thought to interact with nociceptive neuron nerve endings in the skin to directly sense noxious proinflammatory stimuli (79), and also to control TRPV1 channel activity in T cells (38,80). Taken together, the above findings suggest that VDR may play a role in modulating the expression of pain-genes, for example, those involved in the development of neurons and Schwann cells (60,81) as well as ion channels expressed in nociceptor neurons that innervate the skin as discussed above.…”

Investigation of Antinociceptive Effects of Vitamin D and EB1089 in Rats

“…It is thought that vitamin D synthesized in the skin interacts with nociceptive neuron nerve endings in the skin and directly perceives harmful pro-inflammatory stimuli [16] and also controls TRPV1 channel activity in T-cells. [17,18] The studies have mainly focused on chronic and neuropathic pain in the literature and there are limited works on acute pain.…”