Acrosomal Swelling is Triggered by cAMP Downstream of the Opening of Store-Operated Calcium Channels During Acrosomal Exocytosis in Human Sperm1

Abstract

Acrosomal exocytosis in mammalian sperm is a regulated secretion with unusual characteristics. One of its most striking features is the postfusion loss of the outer acrosomal membrane and the overlying plasma membrane as hybrid vesicles. We have previously reported in human sperm that, by preventing the release of calcium from the acrosome, the exocytic process can be arrested at a stage where the acrosomes are profusely swollen, with invaginations of the outer acrosomal membrane. In this report, we show by transmission electron microcopy swelling with similar characteristics without arresting the exocytic process. Acrosomal swelling was observed when secretion was promoted by pharmacological and physiological inducers of the acrosome reaction that trigger exocytosis by different mechanisms. We show that progesterone- and thapsigargin-induced swelling depended on a calcium influx from the extracellular medium through store-operated calcium channels. However, calcium was dispensable when sperm were stimulated with cAMP analogs. KH7, an inhibitor of the soluble adenylyl cyclase, blocked progesterone-induced swelling. Our results indicate that swelling is a required process for acrosomal exocytosis triggered by activation of an adenylyl cyclase downstream of the opening of store-operated calcium channels.

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…(6)-2-(1H-Benzimidazol-2-ylthio)propanoic acid 2-[(5-bromo-2-hydroxyphenyl)methylene]hydrazide (KH7) is the most widely used sAC inhibitor in intact-cell studies (Kumar et al, 2009;Schmid et al, 2010;Kolodecik et al, 2012;Bitterman et al, 2013;Dey et al, 2014;Hasan et al, 2014;Nickols et al, 2015;De Rasmo et al, 2015;Sosa et al, 2016). Caution must be exerted when Pharmacological Modulation of Mammalian Adenylyl Cyclases interpreting intact-cell studies with KH7 because of toxic effects of this compound in mitochondria (Di Benedetto et al, 2013) and b cells (Tian et al, 2011).…”

Acrosomal alkalization triggers Ca2+ release and acrosome reaction in mammalian spermatozoa

“…Considering its similarities with the endolysosomal system, the acrosome has been referred to as a lysosome‐related organelle (Foster & Gerton, ). Acrosomal osmoregulation (Sosa, Zanetti, Pocognoni, & Mayorga, ) is considered an important element of the AR; the acrosome must swell before this reaction occurs (Zanetti & Mayorga, ). In addition, pH acr which increases during capacitation and correlates with spontaneous AR (Nakanishi et al, ; Working & Meizel, , ), has been related to the organization of the acrosomal matrix (Guyonnet, Egge, & Cornwall, ; Huang & Yanagimachi, ).…”

Impact of aluminium toxicity on vital human sperm parameters—Protective effects of silymarin

“…The mechanism by which aluminium induces premature acrosome reaction is yet to be elucidated. Acrosome reaction is a calcium‐dependent exocytosis process (Sosa, Zanetti, Pocognoni, & Mayorga, 2016). Since aluminium increases intracellular calcium concentration in astrocytes (Ruiz‐Pesini et al., 2000), rat brain cortex (Cui et al, 2012) and plant cells (Mariano et al., 2015), one possibility is that aluminium induces an abnormal increase in calcium concentration inside the spermatozoa which can consequently lead to abnormal acrosome reaction.…”