Biology subjects

Stival, C.

Publications and source records attributed to Stival, C..

3 recordsLinked to original sources

bioRxiv2025

SPINK3-sperm interaction determines a stable sperm subpopulation with intact CatSper channel

Sperm capacitation involves proteolytic remodeling of membrane proteins, including components of the CatSper calcium channel, which is essential for hyperactivation and male fertility. Here, we identify the seminal protease inhibitor SPINK3, a known decapacitation factor that suppresses premature capacitation in the female tract, as the first physiological inhibitor of CATSPER1 processing. In mouse sperm, SPINK3 blocks capacitation-induced CATSPER1 cleavage, preserving a subpopulation with intact CatSper channels and lacking pTyr development in the flagellum. SPINK3 localizes to the outer surface of the sperm principal piece membrane in a CatSper-dependent but non-quadrilateral pattern, stabilizes membrane organization, and delays cholesterol efflux. These results reveal SPINK3 as a multifunctional regulator of capacitation, shaping sperm subpopulations in the female reproductive tract. SIGNIFICANCE STATEMENTThis study unveils a novel physiological regulator from the male reproductive tract, SPINK3, which extracellularly controls the processing of CATSPER1, a key subunit of the CatSper calcium channel essential for sperm capacitation in mice. We show that SPINK3 binds to the sperm surface and prevents the processing of CATSPER1 during capacitation. SPINK3-sperm interaction is dependent on the presence of the sperm-specific CatSper channel. Our findings reveal that SPINK3 stabilizes sperm membranes providing new insights into the molecular regulation of sperm function and fertility. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/672324v3_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@164c737org.highwire.dtl.DTLVardef@1531499org.highwire.dtl.DTLVardef@16d7abaorg.highwire.dtl.DTLVardef@945453_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

The sodium-proton exchangers sNHE and NHE1 control plasma membrane hyperpolarization in mouse sperm.

Sperm capacitation, crucial for fertilization, occurs in the female reproductive tract and can be replicated in vitro using a medium rich in bicarbonate, calcium, and albumin. These components trigger the cAMP-PKA signaling cascade, proposed to promote hyperpolarization of the mouse sperm plasma membrane through activation of SLO3 K+ channel. Hyperpolarization is a hallmark of capacitation: proper membrane hyperpolarization renders higher in vitro fertilizing ability, while Slo3 KO mice are infertile. However, the precise regulation of SLO3 opening remains elusive. Our study challenges the involvement of PKA in this event and reveals the role of Na+/H+ exchangers. During capacitation, calcium increase through CatSper channels activates NHE1, while cAMP directly stimulates the sperm-specific NHE, collectively promoting the alkalinization threshold needed for SLO3 opening. Hyperpolarization then feeds back Na+/H+ activity. Our work is supported by pharmacology, and a plethora of KO mouse models, and proposes a novel pathway leading to hyperpolarization. TeaserAlkalinization of sperm cytoplasm activates potassium channels to hyperpolarize the plasma membrane in a PKA independent cascade.

cell biology↗

bioRxiv2020

Cdc42 activity is essential for the interplay between cAMP/PKA pathway and CatSper function

Sperm acquire the ability to fertilize in a process called capacitation and undergo hyperactivation, a change in the motility pattern, which depends on Ca2+ transport by CatSper channels. CatSper is essential for fertilization and it is subjected to a complex regulation that is not fully understood. Here, we report that similar to CatSper, Cdc42 distribution in the principal piece is confined to four linear domains and this localization is disrupted in CatSper1-null sperm. Cdc42 inhibition impaired CatSper activity and other Ca2+-dependent downstream events resulting in a severe compromise of the sperm fertilizing potential. We also demonstrate that Cdc42 is essential for CatSper function by modulating cAMP production by sAC, providing a new regulatory mechanism for the stimulation of CatSper by the cAMP/PKA-dependent pathway. These results reveal a broad mechanistic insight into the regulation of Ca2+ in mammalian sperm, a matter of critical importance in male infertility as well as in contraception.

cell biology↗