Protein Kinase A-anchoring Inhibitor Peptides Arrest Mammalian Sperm Motility

Cilium and flagellum beating are important in reproduction and defects in their motion are associated with ectopic pregnancy and infertility. Adrenomedullin (ADM) is a polypeptide present in the reproductive system. This report demonstrates a novel action of ADM in enhancing the flagellar/ciliary beating of human spermatozoa and rat oviductal ciliated cells. At the concentration found in the seminal plasma, it increases the progressive motility of spermatozoa. ADM binds to its classical receptor, calcitonin receptor-like receptor/receptor activity-modifying protein complex on spermatozoa. ADM treatment increases the protein kinase A activities, the cyclic adenosine monophosphate, and nitric oxide levels of spermatozoa and oviductal cells. Pharmacological activators and inhibitors confirmed that the ADM-induced flagella/ciliary beating was protein kinase A dependent. Whereas nitric oxide donors had no effect on sperm motility, they potentiated the motility-inducing action of protein kinase A activators, demonstrating for the first time the synergistic action of nitric oxide and protein kinase A signaling in flagellar/ciliary beating. The ADM-induced motility enhancement effect in spermatozoa also depended on the up-regulation of intracellular calcium, a known key regulator of sperm motility and ciliary beating. In conclusion, ADM is a common activator of flagellar/ciliary beating. The study provides a physiological basis on possible use of ADM as a fertility regulation drug.

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Silymarin and protein kinase A inhibitor modulate glucose-mediated mouse sperm motility: An in vitro study

Reproductive Biology ◽

10.1016/j.repbio.2015.06.003 ◽

2015 ◽

Vol 15 (3) ◽

pp. 172-177 ◽

Cited By ~ 5

Author(s):

Yi-Chuan Chen ◽

Li-Chern Pan ◽

Cheng-Wei Lai ◽

Ying-Shan Chien ◽

Tzu-Hua Wu

Keyword(s):

Protein Kinase ◽

Protein Kinase A ◽

Sperm Motility ◽

In Vitro Study ◽

Vitro Study ◽

Mouse Sperm ◽

Kinase A

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CatSper channels are regulated by protein kinase A

Journal of Biological Chemistry ◽

10.1074/jbc.ra117.001566 ◽

2018 ◽

Vol 293 (43) ◽

pp. 16830-16841 ◽

Cited By ~ 22

Author(s):

Gerardo Orta ◽

José Luis de la Vega-Beltran ◽

David Martín-Hidalgo ◽

Celia M. Santi ◽

Pablo E. Visconti ◽

...

Keyword(s):

Protein Kinase ◽

Patch Clamp ◽

Protein Kinase A ◽

Intracellular Camp ◽

Sperm Capacitation ◽

Mammalian Sperm ◽

Electrophysiological Recordings ◽

Intracellular Ca ◽

Whole Cell Recordings ◽

Kinase A

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 Ca2+ concentration ([Ca2+]i) is essential for sperm capacitation. Although a cross-talk between cAMP-dependent pathways and Ca2+ 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 Ca2+ 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 [Ca2+]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 [Ca2+]i homeostasis by activating CatSper channel complexes.

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Molecular mechanisms of sperm motility are conserved in an early-branching metazoan

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2109993118 ◽

2021 ◽

Vol 118 (48) ◽

pp. e2109993118

Author(s):

Kelsey F. Speer ◽

Luella Allen-Waller ◽

Dana R. Novikov ◽

Katie L. Barott

Keyword(s):

Protein Kinase ◽

Reproductive Success ◽

Protein Kinase A ◽

Sperm Motility ◽

Molecular Mechanisms ◽

Camp Signaling ◽

Dependent Manner ◽

Marine Animals ◽

Ph Dependent ◽

Kinase A

Efficient and targeted sperm motility is essential for animal reproductive success. Sperm from mammals and echinoderms utilize a highly conserved signaling mechanism in which sperm motility is stimulated by pH-dependent activation of the cAMP-producing enzyme soluble adenylyl cyclase (sAC). However, the presence of this pathway in early-branching metazoans has remained unexplored. Here, we found that elevating cytoplasmic pH induced a rapid burst of cAMP signaling and triggered the onset of motility in sperm from the reef-building coral Montipora capitata in a sAC-dependent manner. Expression of sAC in the mitochondrial-rich midpiece and flagellum of coral sperm support a dual role for this molecular pH sensor in regulating mitochondrial respiration and flagellar beating and thus motility. In addition, we found that additional members of the homologous signaling pathway described in echinoderms, both upstream and downstream of sAC, are expressed in coral sperm. These include the Na+/H+ exchanger SLC9C1, protein kinase A, and the CatSper Ca2+ channel conserved even in mammalian sperm. Indeed, the onset of motility corresponded with increased protein kinase A activity. Our discovery of this pathway in an early-branching metazoan species highlights the ancient origin of the pH-sAC-cAMP signaling node in sperm physiology and suggests that it may be present in many other marine invertebrate taxa for which sperm motility mechanisms remain unexplored. These results emphasize the need to better understand the role of pH-dependent signaling in the reproductive success of marine animals, particularly as climate change stressors continue to alter the physiology of corals and other marine invertebrates.

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