Modulation of the human sperm acrosome reaction by effectors of the adenylate cyclase/cyclic AMP second‐messenger pathway

Abstract

The acrosome reaction of spermatozoa appears to be analogous to various somatic cell exocytotic events which involve cascade reactions, i.e., transmission of an external signal across the cell membrane resulting in activation of an "amplifier" enzyme and the generation of a second messenger. Using a synchronous acrosome reaction system (De Jonge et al., J. Androl., 10:232-239, '89a), it was found that analogues of the second-messenger cAMP, dibutyryl cAMP (dbcAMP) and 8-bromo cAMP, stimulated the acrosome reaction of capacitated spermatozoa. Additionally, treatment of spermatozoa with either xanthine or non-xanthine phosphodiesterase inhibitors induced a significant (P less than 0.05) increase in the percent acrosome reaction after a period of capacitation in comparison to untreated controls. These results indicate that analogues of cAMP or inhibitors which prevent cAMP hydrolysis can induce the human sperm acrosome reaction. Subsequent experiments were conducted to test whether the amplifier enzyme in the cascade reaction, adenylate cyclase, has a role in the acrosome reaction. Forskolin, an adenylate cyclase stimulator, caused a significant (P less than 0.01) increase in the percent acrosome reaction in comparison to controls. Modulators of adenylate cyclase--adenosine, 2'-0-methyladenosine, and 2',3'-dideoxyadenosine--significantly (P less than 0.01) inhibited the forskolin-induced acrosome reaction. dbcAMP was able to overcome the inhibition by adenosine. Two inhibitors of protein kinase A, the Walsh inhibitor and H-8, caused a significant (P less than 0.01) inhibition of the dbcAMP-induced acrosome reaction. Finally, in the absence of extracellular calcium, dbcAMP induced a significant (P less than 0.01) increase in the acrosome reaction in contrast to A23187. These results suggest that: 1) a molecular mechanism for the human sperm acrosome reaction involves the cAMP second-messenger system; i.e., activation of adenylate cyclase, the amplifier enzyme that produces cAMP, production of cAMP as a second messenger, and activation of cAMP-dependent kinase A; and that 2) activation of adenylate cyclase occurs after calcium influx.

Chorionic morphine, naltrexone and pentoxifylline effect on hypophyso-gonadal hormones of male rats

“…Cyclic AMP, in turn, is believed to stimulate the cAMP-dependent kinase (24), which itself induces sperm tail protein phosphorylation (25) with subsequent increase in sperm motility (26). Improving acrosomal reaction is another benefi cial effect of pentoxifylline drug, demonstrated that this induction is not due to a Ca 2+ -infl ux in the sperm cell but is according to increasing the intracellular level of cAMP as the second messenger of acrosomal reaction (27,28).…”

Regulation of acrosome reaction of fowl spermatozoa: evidence for the involvement of protein kinase C and protein phosphatase-type 1 and/or -type 2A

“…The molecular mechanisms and the signal transduction pathways mediating the processes of acrosome reaction are partially defined: changes in protein phosphorylation and dephosphorylation of sperm proteins, including Ca 2C -dependent processes, seem to play a primary role in the second messenger regulatory mechanisms (for a review, see Benoff 1998, Breitbart & Naor 1999, Baldi et al 2000, Guraya 2000, Topfer-Petersen et al 2000, Urner & Sakkas 2003. There is evidence for the involvement of cAMP-dependent protein kinase (PKA) in the mammalian acrosome reaction: adenylate cyclase activity and cAMP generation increased during this process in human spermatozoa (De Jonge et al 1991); adenylate cyclase stimulators such as forskolin, and the cAMP analogue dibutyryl cAMP, induced the acrosome reaction in a dose-dependent manner in human and ram spermatozoa (Anderson et al 1992, Garde & Roldan 2000, Harrison & Meizel 2000; and PKA inhibitors have been reported to suppress human sperm acrosome reaction (Harrison & Meizel 2000).…”

Effects of pentoxifylline treatment before freezing on motility, viability and acrosome status of poor quality human spermatozoa cryopreserved by the liquid nitrogen vapor method

“…PF inhibits cyclic adenosine monophosphate (cAMP) phosphodiesterase, thus increasing intracellular cAMP concentration (5,7) and tyrosine-phosphorylation at the tail level (8). cAMP has a role in sperm kinematics and in the acrosome reaction second-messenger system (7,9). Treatments that increase intracellular cAMP concentrations often cause an increase in sperm motility and kinematics as well as in the agonist-induced acrosome reaction (9) and fertilization rates (5,6).…”

“…cAMP has a role in sperm kinematics and in the acrosome reaction second-messenger system (7,9). Treatments that increase intracellular cAMP concentrations often cause an increase in sperm motility and kinematics as well as in the agonist-induced acrosome reaction (9) and fertilization rates (5,6). Also, it has been postulated that PF has the ability to scavenge reactive oxygen radicals (10,11).…”