INTRODUCTION

Steroid hormones control vital organism functions such as development, metabolism, inflammation, ion homeostasis, and reproduction. According to the conventional model of steroid signaling, these functions are regulated through the interaction of steroid hormones to their corresponding genomic receptor to alter gene expression. The timescale of such events ranges from several hours to days. However, there is another, much faster response that is also triggered by steroid hormones in a separate “non-genomic” manner that is poorly understood. This unconventional non-genomic signaling happens on a timescale of seconds and plays an important role in modulation of pain perception by dorsal root ganglion neurons, and in oocyte maturation, and is vital for human sperm cell activation.

The steroid hormone progesterone (P4) is a major component of follicular fluid and is released by ovaries and cumulus cells surrounding the oocyte. At nanomolar concentrations, P4 is known to cause rapid and robust elevation of sperm cytoplasmic calcium levels through binding to a non-genomic receptor. This rise in intracellular [Ca2+] leads to changes in sperm motility known as hyperactivation and primes the cell for acrosomal exocytosis. It is also proposed that through this rapid signaling mechanism, P4 can serve as a sperm chemoattractant. A critical step in sperm cell activation is a massive P4-mediated calcium influx through a calcium channel CatSper.

SUMMARY

The present disclosure provides compositions and methods of modulating abhydrolase domain-containing protein-2 (ABHD2). The present disclosure provides methods of identifying agents that modulate ABHD2 activity.

