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Functional studies on mouse SEMG1 as a modulator of CatSper in sperm flagellum

Grant number: 22/10159-6
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): February 23, 2023
Effective date (End): August 22, 2023
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Erick José Ramo da Silva
Grantee:Noemia Aparecida Partelli Mariani
Supervisor: Polina V. Lishko
Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Research place: Washington University in St. Louis, United States  
Associated to the scholarship:20/04841-3 - Study of EPPIN as sperm target for male contraception: structural characterization, protein-protein interaction and potential mechanisms of action, BP.DR

Abstract

After ejaculation, mammalian spermatozoa need to undergo several molecular and biochemistry changes to fertilize the egg. The major protein of the seminal plasma is semenogelin 1 (SEMG1), which plays several roles in the modulation of sperm function, such as motility, hyperactivation and capacitation. SEMG1 modulates sperm function by interacting with EPPIN, a cysteine-rich protein found in spermatozoa from several species, including humans and mice. Previously, we showed that the EPPIN protein-protein interaction network in murine spermatozoa is similar to humans by the elucidation that mouse SEMG1 (mSEMG1) is an EPPIN interacting protein on the mouse sperm surface. However, the underlying mechanisms by which SEMG1/EPPIN binding governs sperm function and fertility potential are not clarified. It is recognized that ion transport by channels and transporters across the plasma membrane is a crucial event for sperm function. In this scenario, the Ca2+ transport mediated by the CatSper channel complex is crucial for the regulation of sperm motility and hyperactivation. Previous studies demonstrated that both SEMG1 and anti-EPPIN antibodies targeting the SEMG1 binding site induce the inhibition of human sperm motility associated with loss of intracellular Ca2+ and a decrease in intracellular pH. However, the involvement of the CatSper channel in the loss of calcium by SEMG1 is still unclear. Here, we propose to investigate whether SEMG1 inhibits sperm hyperactivation by modulating the CatSper channel complex using murine spermatozoa as experimental models. Our specific aims are: 1) to elucidate whether mSEMG1 mediates the loss of calcium levels by modulating the CatSper channel in mouse sperm flagellum; and 2) to identify the mSEMG1 sequence that mediates the modulation of the CatSper channel. Our proposal is innovative and relevant since it will contribute to advancing the studies focusing on the modulation of the main Ca2+ channel of sperm flagellum and demonstrate the potential of mSEMG1 as a prototype of a new male contraceptive targeting the inhibition of sperm hyperactivation. (AU)

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