[Seminar] Ion Channels of Communication in Mouse Sperm

Title: Ion Channels of Communication in Mouse Sperm

Speaker: Alberto Darszon

From: Instituto de Biotecnología, Universidad Nacional Autónoma de México

Abstract:

Capacitation is a maturation process required for mammalian sperm to fertilize the egg. It involves changes in membrane potential (Em) and elevations in cytoplasmic calcium ([Ca²⁺]i), intracellular pH (pHi), and acrosomal pH (pHa), together with orchestrated changes in ion permeability that prepare sperm for the acrosome reaction (AR). The acrosome is a lysosome-related vesicle in the sperm head whose exocytosis, the AR, is Ca²⁺-dependent and essential for fertilization.

Recent evidence highlights the role of pHa alkalinization in AR induction. Amphipathic weak bases accumulate in the acrosome, elevate pHa, raise [Ca²⁺]i, and stimulate AR. Using single-cell Ca²⁺ imaging and pharmacological tools, we found that Mibefradil (Mib) and NNC, two amphipathic weak bases, trigger acrosomal Ca²⁺ release without compromising acrosomal integrity. Inhibition of two-pore channel 1 (TPC1) reduced the [Ca²⁺]i increase caused by pHa alkalinization, while blockade of Ca²⁺ release–activated Ca²⁺ (CRAC) channels diminished extracellular Ca²⁺ entry. Together, these results uncover a mechanism by which pHa controls both acrosomal Ca²⁺ efflux and extracellular Ca²⁺ influx during AR in mouse sperm.

We recently reported that transient nutrient deprivation (starvation, STRV) partly resembles capacitation: it elevates [Ca²⁺]i, alkalinizes pHi and pHa, enhances progesterone-induced AR, and improves assisted reproduction outcomes. Our whole-cell patch-clamp recordings revealed that STRV enhances Ca²⁺-activated chloride currents, which were reversed by glucose supplementation. These currents were Ca²⁺-dependent, abolished by the chelator BAPTA-AM, sensitive to CaCC inhibitors (niflumic acid, T16Ainh-A01, MONNA), and partially mediated by CFTR. Importantly, blocking TMEM16A before capacitation inhibited the hyperactivated motility that is required for sperm to progress through the female tract.

These findings establish acrosomal alkalinization and nutrient status as key regulators of Ca²⁺ fluxes and Ca²⁺-activated chloride channel activity in mouse sperm. They provide new insights into how ion channel modulation coordinates capacitation and AR, thereby contributing to fertilization success.