First messenger regulation of capacitation via G protein-coupled mechanisms: a tale of serendipity and discovery.

When placed in a suitable environment, mammalian spermatozoa begin to capacitate and continue until fully capacitated; in vitro, some will 'over-capacitate' and undergo spontaneous acrosome loss, undesirable since acrosome-reacted cells are non-fertilizing. Seminal plasma contains several molecules able to bind to specific receptors on spermatozoa, thereby activating/regulating important intracellular signalling pathways. Three such 'first messengers' are fertilization promoting peptide (FPP), adenosine and calcitonin, all of which stimulate capacitation and then inhibit spontaneous acrosome reactions by regulating adenylyl cyclase (AC)/cAMP. A recent study has reported the presence in spermatozoa of several membrane-associated AC isoforms, mainly smaller in size than the corresponding ACs in somatic cells, and evidence suggests that more than one of these isoforms may be involved in responses to these first messengers. To regulate AC, FPP receptors appear to interact initially with stimulatory A(2A) adenosine receptors, which function only in uncapacitated cells, and then with inhibitory A(1) receptors, which function only in capacitated cells. In contrast, there appears to be a single population of calcitonin receptors. Responses to cholera and pertussis toxins suggest involvement of G proteins and G(s) plus several G(i) subunits have been identified in both mouse and human spermatozoa. In particular, Galpha(s) and Galpha(i2) are found in the same regions as FPP, adenosine and calcitonin receptors, supporting biochemical evidence for G protein involvement in these responses. In vivo, these first messengers could have a significant effect, helping to maximize the number of capacitated, acrosome-intact (i.e. potentially fertilizing) spermatozoa by regulating what is clearly an important signalling pathway.