Abstract
Sex hormone steroidal drugs were reported to have modulating actions on the ion channel TRPM3. Pregnenolone sulphate (PS) presents the most potent known endogenous chemical agonist of TRPM3 and affects several gating modes of the channel. These includes a synergistic action of PS and high temperatures on channel opening and the PS-induced opening of a noncanonical pore in the presence of other TRPM3 modulators. Moreover, human TRPM3 variants associated with neurodevelopmental disease exhibit an increased sensitivity for PS. However, other steroidal sex hormones were reported to influence TRPM3 functions with activating or inhibiting capacity. Here, we aimed to answer how DHEAS, estradiol, progesterone and testosterone act on the various modes of TRPM3 function in the wild-type channel and two-channel variants associated with human disease. By means of calcium imaging and whole-cell patch clamp experiments, we revealed that all four drugs are weak TRPM3 agonists that share a common steroidal interaction site. Furthermore, they exhibit increased activity on TRPM3 at physiological temperatures and in channels that carry disease-associated mutations. Finally, all steroids are able to open the noncanonical pore in wild-type and DHEAS also in mutant TRPM3. Collectively, our data provide new valuable insights in TRPM3 gating, structure-function relationships and ligand sensitivity.
Highlights
Sex hormones control several crucial body functions as they act on multiple different tissues in our endocrine and nervous system
At 23 ◦ C, 300 μM dehydroepiandrosterone sulphate (DHEAS) and E2 could elicit a moderate increase in [Ca2+ ]i (Figure 2A,C) while only a limited rise in intracellular calcium levels was observed for 300 μM P4 or T (Figure 2E,G)
In case of 300 μM DHEAS at 37 ◦ C, a robust and reversible increase of the intracellular calcium levels was observed, which was not detected in Nontransfected HEK293T (NT) cells (Figure 2A)
Summary
Sex hormones control several crucial body functions as they act on multiple different tissues in our endocrine and nervous system. These actions occur primarily via the classical genomic pathway, which requires the involvement of nuclear receptors that intracellularly bind these sex hormones and subsequently affect gene transcription mechanisms [1,2]. One family of proteins comprising such membrane receptors is the superfamily of transient receptor potential (TRP) channels. This class of cationic permeable ion channels are membrane-spanning proteins that are responsive to a diverse range of stimuli including physical, thermal as well as chemical cues. It has been already reported that some members are modulated by steroid sex hormones, including TRPM8 by testosterone, TRPA1 and TRPV1 by androstenedione [5,6,7], as well as TRPM3 by a limited number of steroids [8]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call