| First Author | Orta G | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 43 | Pages | 16830-16841 |
| PubMed ID | 30213858 | Mgi Jnum | J:270275 |
| Mgi Id | MGI:6268505 | Doi | 10.1074/jbc.RA117.001566 |
| Citation | Orta G, et al. (2018) CatSper channels are regulated by protein kinase A. J Biol Chem 293(43):16830-16841 |
| abstractText | Mammalian sperm must undergo capacitation as a preparation for entering into hyperactivated motility, undergoing the acrosome reaction, and acquiring fertilizing ability. One of the initial capacitation events occurs when sperm encounter an elevated HCO3 (-) concentration. This anion activates the atypical adenylyl cyclase Adcy10, increases intracellular cAMP, and stimulates protein kinase A (PKA). Moreover, an increase in intracellular Ca(2+) concentration ([Ca(2+)] i ) is essential for sperm capacitation. Although a cross-talk between cAMP-dependent pathways and Ca(2+) clearly plays an essential role in sperm capacitation, the connection between these signaling events is incompletely understood. Here, using three different approaches, we found that CatSper, the main sperm Ca(2+) channel characterized to date, is up-regulated by a cAMP-dependent activation of PKA in mouse sperm. First, HCO3 (-) and the PKA-activating permeable compound 8-Br-cAMP induced an increase in [Ca(2+)] i , which was blocked by the PKA peptide inhibitor PKI, and H89, another PKA inhibitor, also abrogated the 8-Br-cAMP response. Second, HCO3 (-) increased the membrane depolarization induced upon divalent cation removal by promoting influx of monovalent cations through CatSper channels, which was inhibited by PKI, H89, and the CatSper blocker HC-056456. Third, electrophysiological patch clamp, whole-cell recordings revealed that CatSper activity is up-regulated by HCO3 (-) and by direct cAMP injection through the patch-clamp pipette. The activation by HCO3 (-) and cAMP was also blocked by PKI, H89, Rp-cAMPS, and HC-056456, and electrophysiological recordings in sperm from CatSper-KO mice confirmed CatSper's role in these activation modes. Our results strongly suggest that PKA-dependent phosphorylation regulates [Ca(2+)] i homeostasis by activating CatSper channel complexes. |
