ArticleThe Journal of biological chemistry2009
Epac activates the small G proteins Rap1 and Rab3A to achieve exocytosis.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 95 citations in OpenAlex.
- Ca2+ signals generated by CatSper and Ca2+ stores regulate different behaviors in human sperm.The Journal of biological chemistry · 2013Trial
- The effect and mechanism of total alkaloids ofFrontiers in pharmacology · 2026Article
- RAP1-GTPase immunostaining is altered in human precancerous and cancerous cervical lesions.Biomarkers in medicine · 2024Article
- Lipid remodeling in acrosome exocytosis: unraveling key players in the human sperm.Frontiers in cell and developmental biology · 2024Review
- Mechanisms That Protect Mammalian Sperm from the Spontaneous Acrosome Reaction.International journal of molecular sciences · 2023Review
- CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors.Breast cancer (Tokyo, Japan) · 2022Article
- Talin‑1 interaction network in cellular mechanotransduction (Review).International journal of molecular medicine · 2022Review
- Tetraspanins: Host Factors in Viral Infections.International journal of molecular sciences · 2021Review
- Article
- Adrenergic stimulation of adiponectin secretion in visceral mouse adipocytes is blunted in high-fat diet induced obesity.Scientific reports · 2019Article
- Article
- Super-resolution imaging of live sperm reveals dynamic changes of the actin cytoskeleton during acrosomal exocytosis.Journal of cell science · 2018Article
- Pharmacological modulation of the COPharmacology & therapeutics · 2018Review
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- Molecular Basis of Human Sperm Capacitation.Frontiers in cell and developmental biology · 2018Review
- How Rap and its GEFs control liver physiology and cancer development. C3G alterations in human hepatocarcinoma.Hepatic oncology · 2018Review
- Inhibition of Epac2 Attenuates Neural Cell Apoptosis and Improves Neurological Deficits in a Rat Model of Traumatic Brain Injury.Frontiers in neuroscience · 2018Article
- The dynamic plasticity of insulin production in β-cells.Molecular metabolism · 2017Review
- Rab3a-Bound CD63 Is Degraded and Rab3a-Free CD63 Is Incorporated into HIV-1 Particles.Frontiers in microbiology · 2017Article
- Host Epac1 is required for cAMP-mediated invasion by Trypanosoma cruzi.Molecular and biochemical parasitology · 2017Article
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Exocytosis of the acrosome (the acrosome reaction) relies on cAMP production, assembly of a proteinaceous fusion machinery, calcium influx from the extracellular medium, and mobilization from inositol 1,4,5-trisphosphate-sensitive intracellular stores. Addition of cAMP to human sperm suspensions bypasses some of these requirements and elicits exocytosis in a protein kinase A- and extracellular calcium-independent manner. The relevant cAMP target is Epac, a guanine nucleotide exchange factor for the small GTPase Rap. We show here that a soluble adenylyl cyclase synthesizes the cAMP required for the acrosome reaction. Epac stimulates the exchange of GDP for GTP on Rap1, upstream of a phospholipase C. The Epac-selective cAMP analogue 8-pCPT-2'-O-Me-cAMP induces a phospholipase C-dependent calcium mobilization in human sperm suspensions. In addition, our studies identify a novel connection between cAMP and Rab3A, a secretory granule-associated protein, revealing that the latter functions downstream of soluble adenylyl cyclase/cAMP/Epac but not of Rap1. Challenging sperm with calcium or 8-pCPT-2'-O-Me-cAMP boosts the exchange of GDP for GTP on Rab3A. Recombinant Epac does not release GDP from Rab3A in vitro, suggesting that the Rab3A-GEF activation by cAMP/Epac in vivo is indirect. We propose that Epac sits at a critical point during the exocytotic cascade after which the pathway splits into two limbs, one that assembles the fusion machinery into place and another that elicits intracellular calcium release.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.