Pregnenolone Sulfate: From Steroid Metabolite to TRP Channel Ligand

Abstract

Pregnenolone sulfate is a steroid metabolite with a plethora of actions and functions. As a neurosteroid, pregnenolone sulfate modulates a variety of ion channels, transporters, and enzymes. Interestingly, as a sulfated steroid, pregnenolone sulfate is not the final-or waste-product of pregnenolone being sulfated via a phase II metabolism reaction and renally excreted, as one would presume from the pharmacology textbook knowledge. Pregnenolone sulfate is also the source and thereby the starting point for subsequent steroid synthesis pathways. Most recently, pregnenolone sulfate has been functionally "upgraded" from modulator of ion channels to an activating ion channel ligand. This review will focus on molecular aspects of the neurosteroid, pregnenolone sulfate, its metabolism, concentrations in serum and tissues and last not least will summarize the functional data.

Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids

“…To evaluate whether PregS activated CatSper, we inhibited PregS-elicited currents with 1 μM NNC 55-0396, a known CatSper inhibitor (3) (Fig. 2 A and B (14). It is also abundant in testes, in which the total PregS concentrations can reach 2.8 μmol/kg (3.8 μM), whereas it drops to 0.76 μmol/kg (190 nM) in the epididymis (14).…”

“…2 A and B (14). It is also abundant in testes, in which the total PregS concentrations can reach 2.8 μmol/kg (3.8 μM), whereas it drops to 0.76 μmol/kg (190 nM) in the epididymis (14). Such high PregS concentrations may result in premature CatSper activation, while spermatozoa are still in the male reproductive tract, which would be detrimental for sperm fertility.…”

“…The female hormone progesterone (P4) activates the principal calcium channel of sperm (CatSper) (2)(3)(4)(5) and blocks the potassium channel KSper (6) via these nongenomic pathways (7). The modulation of ion channel functions by steroid hormones has been reported in the heart (8,9), neurons (10)(11)(12), smooth muscle (13), and pancreatic beta cells (14). In marine invertebrates, the sulfated steroid cholestane acts as a chemoattractant for sea squirt sperm, which also happens via the nongenomic pathway (15).…”

“…The latter represents an unconventional chemoattractant for ascidian sperm, as such factors are usually proteins or peptides and not steroids. In humans, pregnenolone sulfate (PregS), a sulfated steroid hormone similar in structure to P4, is a nongenomic activator of the transient receptor potential cation channel subfamily M member 3 (TRPM3) channel in pancreatic beta cells (14). However, the precise mechanism of this activation is unknown.…”

The chemical composition and sensory properties of raw, cooked and grilled thigh meat of broiler chickens fed with Fe-Gly chelate

“…However, it can be supposed that Fe in an easily assimilable organic form has a more effective influence on lipid transformations in the animal body than inorganic Fe. Iron is a part of adrenodoxin-one of the components of the cholesterol desmolase complex triggering the transformation of cholesterol into pregnenolone (Harteneck 2013). It has been shown that the rate at which cholesterol is converted into pregnenolone depends on the concentration of adrenodoxin (Tuckey and Headlam 2002).…”