Mammalian sperm are not able to fertilize eggs immediately after ejaculation. They acquire fertilization capacity in the female tract in a process known as capacitation. Initially, capacitation was defined using fertilization as an end-point. However, a variety of evidence suggests that the functional changes occurring in the sperm during capacitation are not one event, but a combination of sequential and concomitant processes. These processes are associated with changes in the motility pattern (e.g. hyperactivation) and with preparation of sperm to undergo an agonist-stimulated acrosome reaction. At the molecular level, capacitation is associated with the activation of a cAMP signaling pathway, increase in intracellular pH, changes in the sperm plasma membrane potential, increase in tyrosine phosphorylation and with up-regulation of intracellular Ca2+ concentration ([Ca2+]i). In particular Ca2+ plays central roles in the regulation of both hyperactivation and the AR. However, the molecular mechanisms that control [Ca2+]i in sperm are not well established. The central hypothesis underlying this proposal posits that hyperactivation is the consequence of crosstalk between cAMP and Ca2+-depending signaling pathways. The objective of this proposal is to understand how Ca2+ and other signaling pathways (e.g. increase in pHi, cAMP and changes in Em) integrate during capacitation.

Public Health Relevance

Difficulties in earlier efforts to fertilize mammalian eggs in vitro were due mainly to a lack of comprehension of sperm physiology. This proposal is aimed to understand the molecular basis of sperm capacitation with emphasis in the regulation of the crosstalk between Ca2+ homeostasis and other signaling pathways in sperm. Accomplishment of these goals will provide tools for improving current Assisted Reproductive Technology (ART) methods and to identify novel contraceptive targets.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD038082-12A1
Application #
8697214
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Moss, Stuart B
Project Start
2000-07-01
Project End
2019-03-31
Budget Start
2014-06-02
Budget End
2015-03-31
Support Year
12
Fiscal Year
2014
Total Cost
$312,770
Indirect Cost
$100,660
Name
University of Massachusetts Amherst
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
López-González, I; Torres-Rodríguez, P; Sánchez-Carranza, O et al. (2014) Membrane hyperpolarization during human sperm capacitation. Mol Hum Reprod 20:619-29
Sánchez-Cárdenas, Claudia; Servín-Vences, Martha Rocio; José, Omar et al. (2014) Acrosome reaction and Ca²? imaging in single human spermatozoa: new regulatory roles of [Ca²?]i. Biol Reprod 91:67
Nishigaki, Takuya; José, Omar; González-Cota, Ana Laura et al. (2014) Intracellular pH in sperm physiology. Biochem Biophys Res Commun 450:1149-58
Beltrán, Carmen; Rodríguez-Miranda, Esmeralda; Granados-González, Gisela et al. (2014) Zn(2+) induces hyperpolarization by activation of a K(+) channel and increases intracellular Ca(2+) and pH in sea urchin spermatozoa. Dev Biol 394:15-23
Krapf, Dario; O'Brien, Emma; Maidagán, Paula M et al. (2014) Calcineurin regulates progressive motility activation of Rhinella (Bufo) arenarum sperm through dephosphorylation of PKC substrates. J Cell Physiol 229:1378-86
Chávez, Julio César; Ferreira, Juan José; Butler, Alice et al. (2014) SLO3 K+ channels control calcium entry through CATSPER channels in sperm. J Biol Chem 289:32266-75
Buffone, Mariano G; Wertheimer, Eva V; Visconti, Pablo E et al. (2014) Central role of soluble adenylyl cyclase and cAMP in sperm physiology. Biochim Biophys Acta 1842:2610-20
Battistone, M A; Alvau, A; Salicioni, A M et al. (2014) Evidence for the involvement of proline-rich tyrosine kinase 2 in tyrosine phosphorylation downstream of protein kinase A activation during human sperm capacitation. Mol Hum Reprod 20:1054-66
Chavez, Julio C; de la Vega-Beltran, Jose L; Escoffier, Jessica et al. (2013) Ion permeabilities in mouse sperm reveal an external trigger for SLO3-dependent hyperpolarization. PLoS One 8:e60578
Battistone, M A; Da Ros, V G; Salicioni, A M et al. (2013) Functional human sperm capacitation requires both bicarbonate-dependent PKA activation and down-regulation of Ser/Thr phosphatases by Src family kinases. Mol Hum Reprod 19:570-80

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