Sex difference in TRPM3 channel functioning in nociceptive and vascular systems: an emerging target for migraine therapy in females?

Transient Receptor Potential Melastatin 3 (TRPM3) channels are Ca²⁺ permeable ion channels that act as polymodal sensors of mechanical, thermal, and various chemical stimuli. TRPM3 channels are highly expressed in the trigeminovascular system, including trigeminal neurons and the vasculature. Their presence in dural afferents suggests that they are potential triggers of migraine pain, which is originating from the meningeal area. This area is densely innervated by autonomous and trigeminal nerves that contain the major migraine mediator calcitonin gene-related peptide (CGRP) in peptidergic nerve fibers. Co-expression of TRPM3 channels and CGRP receptors in meningeal nerves suggests a potential interplay between both signalling systems. Compared to other members of the TRP family, TRPM3 channels have a high sensitivity to sex hormones and to the endogenous neurosteroid pregnenolone sulfate (PregS). The predominantly female sex hormones estrogen and progesterone, of which the levels drop during menses, act as natural inhibitors of TRPM3 channels, while PregS is a known endogenous agonist of these channels. A decrease in sex hormone levels has also been suggested as trigger for attacks of menstrually-related migraine. Notably, there is a remarkable sex difference in TRPM3-mediated effects in trigeminal nociceptive signalling and the vasculature. In line with this, the relaxation of human isolated meningeal arteries induced by the activation of TRPM3 channels is greater in females. Additionally, the sex-dependent vasodilatory responses to CGRP in meningeal arteries seem to be influenced by age-related hormonal changes, which could contribute to sex differences in migraine pathology. Consistent with these observations, activation of TRPM3 channels triggers nociceptive sensory firing much more prominently in female than male mouse meninges, suggesting that pain processing in female patients with migraine may differ. Overall, the combined TRPM3-related neuronal and vascular mechanisms could provide a possible explanation for the higher prevalence and even the more severe quality of migraine attacks in females. This narrative review summarizes recent data on the sex-dependent roles of TRPM3 channels in migraine pathophysiology, the potential interplay between TRPM3 and CGRP signalling, and highlights the prospects for translational therapies targeting TRPM3 channels, which may be of particular relevance for women with migraine.