Vitamin D is an endogenous partial agonist of the transient receptor potential vanilloid 1 channel

Abstract

r 25-Hydroxyvitamin D (25OHD) is a partial agonist of TRPV1 whereby 25OHD can weakly activate TRPV1 yet antagonize the stimulatory effects of the full TRPV1 agonists capsaicin and oleoyl dopamine. r 25OHD binds to TRPV1 within the same vanilloid binding pocket as capsaicin. r 25OHD inhibits the potentiating effects of PKC-mediated TRPV1 activity. r 25OHD reduces T-cell activation and trigeminal neuron calcium signalling mediated by TRPV1 activity. r These results provide evidence that TRPV1 is a novel receptor for the biological actions of vitamin D in addition to the well-documented effects of vitamin D upon the nuclear vitamin D receptor. r The results may have important implications for our current understanding of certain diseases where TRPV1 and vitamin D deficiency have been implicated, such as chronic pain and autoimmune diseases, such as type 1 diabetes.

TRPV1 channels as a newly identified target for vitamin D

“…While the classical 1,25OHD/VDR axis underlies many of the observed effects of vitamin D, the evidence presented above indicates that additional cellular targets may mediate some of the documented effects of this vitamin. In this regard, our group recently discovered that TRPV1 channel activity is regulated by physiological nanomolar concentrations of both 25OHD and 1,25OHD, where they act as partial agonists of TRPV1 [ 16 ].…”

“…With respect to vitamin D and ion channel function, our laboratory has recently provided strong evidence that vitamin D can also directly act on the Transient Receptor Potential (TRP) Vanilloid family 1 (TRPV1) channel, a member of the TRP superfamily of ion channels [ 16 ]. Vitamin D has been shown to negatively regulate N-methyl-D-aspartate (NMDA) receptors, kainate receptors, and neuronal L-type voltage-sensitive calcium channels and may therefore confer neuroprotection [ 17 , 18 ].…”

TRPV1 channel as the membrane vitamin D receptor: solving part of the puzzle

“…In a recent issue of The Journal of Physiology , Long et al . (2020) presented the transient receptor potential channel subfamily vanilloid member 1 (TRPV1) as the receptor of vitamin D on the plasma membrane, with compelling evidence from calcium imaging, electrophysiology, docking and functional studies. The authors reported vitamin D as a partial agonist of TRPV1.…”

“…Long et al . (2020) demonstrated that physiologically relevant levels (100 n M ) of 25OHD induce calcium influx and TRPV1 currents into HEK293T cells expressing human TRPV1. This response, mediated by 25OHD alone, was nearly 10% of the response initiated by the TRPV1‐specific exogenous agonist capsaicin (CAP) and its endogenous agonist oleoyl dopamine (OLDA).…”

“…Long et al . (2020) showed that vitamin D treatment is able to block the T cell receptor‐mediated upregulation of IFNγ and TNFα. This effect is likely via TRPV1 inhibition by vitamin D. However, further studies are necessary to establish the role of vitamin D and TRPV1 interaction in differentiation and effector function of T cells under pathological conditions.…”