Soluble adenylyl cyclase (sAC) is indispensable for sperm function and fertilization

Area of Science:

• Reproductive Biology
• Molecular Endocrinology
• Sperm Physiology

Background:

• Soluble adenylyl cyclase (sAC) plays a role in sperm function.
• Male mice lacking sAC are sterile and exhibit impaired sperm motility.
• sAC deficiency affects sperm's ability to fertilize eggs.

Purpose of the Study:

• To investigate the specific functions of cAMP signaling mediated by sAC in spermatozoa.
• To elucidate the role of sAC in sperm capacitation and energy balance.
• To understand the molecular mechanisms underlying sAC-dependent male infertility.

Main Methods:

• Analysis of spermatozoa from sAC-deficient (sAC(-/-)) and wild-type mice.
• Measurement of adenylyl cyclase activity and cAMP content in sperm.
• Assessment of sperm motility, flagellar beat frequency, and Ca(2+) entry.
• Evaluation of protein tyrosine phosphorylation patterns.
• Fertilization assays with zona-intact and zona-free oocytes.

Main Results:

• sAC(-/-) spermatozoa show significantly diminished adenylyl cyclase activity and cAMP levels.
• HCO(3)(-) stimulation fails to rapidly enhance flagellar beat or Ca(2+) entry in sAC(-/-) sperm.
• Key capacitation events, including tyrosine phosphorylation and hyperactivated motility, are impaired in sAC(-/-) sperm.
• sAC(-/-) sperm can fertilize zona-free oocytes, indicating sAC is not required for gamete fusion.
• Reduced ATP levels in sAC(-/-) sperm suggest impaired energy balance.
• Exogenous cAMP analog (cAMP-AM ester) partially rescues motility and phosphorylation defects.

Conclusions:

• sAC is essential for cAMP production in spermatozoa, coordinating cellular energy balance and sperm function.
• Defective cAMP signaling due to sAC absence prevents critical components of sperm capacitation.
• sAC deficiency leads to male infertility by disrupting multiple sperm functions necessary for fertilization.