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Protein kinase enzymes in the human vagina—relation to key mediators of the cyclic AMP and cyclic GMP pathways

Abstract

Aside from phosphodiesterase (PDE) isoenzymes, protein kinases (cAK=cyclic AMP-binding protein kinase, cGK=cyclic GMP-binding protein kinase) have also been identified as important receptors for cyclic nucleotides. A significance of protein kinases in the control of the function of the male and female reproductive tract has been suggested; however, up until today, only a few approaches have addressed these enzymes in female genital tissues. The present study aimed to investigate by means of biochemical and immunohistochemical methods the expression of cAK and cGK. The distribution of cAK(I) and cGK(I) in relation to the vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and PDE type 4 (PDE4) was also evaluated. Cytosolic supernatants prepared from specimens of vaginal wall smooth muscle or epithelium were subjected to anion exchange chromatography and the activities of cAK and cGK(I) measured. To evaluate the distribution of cAK(I) and cGK(I) in relation to VIP, CGRP and PDE4, immunohistochemistry was conducted in sections of the human vaginal wall (full-wall specimens). Activities representing cGK(I) and cAK(I) were resolved from the chromatography column. Staining specific for cAK(Iα) was identified in both vascular and non-vascular vaginal smooth musculature, immunoreactivity for cGK(Iβ) was observed in the smooth muscle and endothelium of small arteries interspersing the sections. cAK(Iα)-positive vessels were found innervated by slender varicose nerve fibers presenting the expression of VIP and CGRP. These arteries also expressed PDE4. Localization of cAK and cGK in close relation to key mediators of the cyclic AMP (PDE4, VIP) and cyclic GMP (CGRP) pathways indicate that both signaling systems may synergistically work together in human vaginal tissue.

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References

  1. 1

    Basson R . A model of women's sexual arousal. J Sex Marital Res 2002; 28: 1–10.

    Article  Google Scholar 

  2. 2

    Munarriz R, Kim NN, Goldstein I, Traish AM . Biology of female sexual function. Urol Clin North Am 2002; 29: 685–693.

    Article  Google Scholar 

  3. 3

    Andersson KE . Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev 2011; 63: 811–859.

    CAS  Article  Google Scholar 

  4. 4

    Burnett AL, Calvin DC, Silver RI, Peppas DS, Docimo SG . Immunohistochemical description of nitric oxide synthase isoforms in human clitoris. J Urol 1997; 158: 75–78.

    CAS  Article  Google Scholar 

  5. 5

    Hoyle CH, Stones RW, Robson T, Whitley K, Burnstock G . Innervation of the vasculature and the microvasculature of the human vagina by NOS and neuropeptide-containing nerves. J Anat 1996; 188: 633–644.

    PubMed  PubMed Central  Google Scholar 

  6. 6

    Kim SW, Jeong SJ, Kim NN, Traish AM . Role of the nitric oxide—cyclic GMP pathway in regulation of vaginal blood flow. Int J Impot Res 2003; 15: 355–361.

    CAS  Article  Google Scholar 

  7. 7

    Francis SH, Corbin JD . Cyclic nucleotide-dependent protein kinases: intracellular receptors for cAMP and cGMP action. Crit Rev Clin Lab Sci 1999; 36: 275–328.

    CAS  Article  Google Scholar 

  8. 8

    Surks HK, Mochizuki N, Kasai Y, Georgescu SP, Tang KM, Ito M et al. Regulation of myosin phosphatase by a specific interaction with cGMP-dependent protein kinase Iα. Science 1999; 286: 1583–1587.

    CAS  Article  Google Scholar 

  9. 9

    Sauzeau V, Le Jeune H, Cario-Toumaniantz C, Smolenski A, Lohmann SM, Bertoglio J et al. Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem 2000; 275: 21722–21729.

    CAS  Article  Google Scholar 

  10. 10

    Andersson KE . Erectile physiological and pathophysiological pathways involved in erectile dysfunction. J Urol 2003; 170: S6–S14.

    Article  Google Scholar 

  11. 11

    D'Amati G, Di Gioia CR, Giordano D, Giorgi M, Dolci S, Jannini EA . Type 5 phosphodiesterase expression in the human vagina. Urology 2002; 60: 191–195.

    Article  Google Scholar 

  12. 12

    Ückert S, Oelke M, Waldkirch ES, Stief CG, Albrecht K, Tröger HD et al. Cyclic adenosine monophosphate and cyclic guanosine monophosphate phosphodiesterase isoenzymes in the human vagina: relation to nitric oxide synthase isoforms and vasoactive intestinal polypeptide containing nerves. Urology 2005; 65: 604–610.

    Article  Google Scholar 

  13. 13

    Ückert S, Waldkirch ES, Albrecht K, Sonnenberg J, Langnaese K, Richter K et al. Expression and distribution of cyclic AMP- and cyclic GMP-binding protein kinases in the human vagina—an immunohistochemical study. J Sex Med 2010; 7: 888–895.

    Article  Google Scholar 

  14. 14

    Berman JR, Bassuk J . Physiology and pathophysiology of female sexual function and dysfunction. World J Urol 2002; 20: 111–118.

    Article  Google Scholar 

  15. 15

    Burnett AL, Goldstein I, Andersson KE, Argiolas A, Christ G, Park K et al. Future sexual medicine physiological treatment targets. J Sex Med 2010; 7: 3269–3304.

    CAS  Article  Google Scholar 

  16. 16

    Klotz T, Bloch W, Zimmermann J, Ruth P, Engelmann U, Addicks K . Soluble guanylate cyclase and cGMP-dependent protein kinase I expression in the human corpus cavernosum. Int J Impot Res 2000; 12: 157–164.

    CAS  Article  Google Scholar 

  17. 17

    Waldkirch ES, Ückert S, Sigl K, Imkamp F, Langnaese K, Richter K et al. Expression and distribution of cyclic GMP-dependent protein kinase-1 (cGK1) isoforms in human penile erectile tissue. J Sex Med 2008; 5: 536–543.

    CAS  Article  Google Scholar 

  18. 18

    Waldkirch ES, Ückert S, Sigl K, Satzger I, Geismar U, Langnaese K et al. Expression of cyclic AMP-dependent protein kinase isoforms in human cavernous arteries: functional significance and relation to phosphodiesterase type 4. J Sex Med 2010; 7: 2104–2011.

    CAS  Article  Google Scholar 

  19. 19

    Feil R, Gappa N, Rutz M, Schlossmann J, Rose CR, Konnerth A et al. Functional reconstitution of vascular smooth muscle cells with cGMP-dependent protein kinase I isoforms. Circ Res 2002; 90: 1080–1086.

    CAS  Article  Google Scholar 

  20. 20

    Castiglione F, Bergamini A, Russo A, La Croce G, Castagna G, Colciago G et al. Inhibition of phosphodiesterase 4 enhances clitoral and vaginal blood flow responses to dorsal clitoral nerve stimulation or PGE1 in anesthetized female rats. J Sex Med 2013; 10: 939–950.

    CAS  Article  Google Scholar 

  21. 21

    Gagnon AW, Aiyar N, Elshourbagy NA . Molecular cloning and functional characterization of a human liver vasoactive intestinal peptide receptor. Cell Signal 1994; 6: 321–333.

    CAS  Article  Google Scholar 

  22. 22

    Casey ML, Smith J, Alsabrook G, MacDonald PC . Activation of adenylyl cyclase in human myometrial smooth muscle cells by neuropeptides. J Clin Endocrinol Metab 1997; 82: 3087–3092.

    CAS  PubMed  Google Scholar 

  23. 23

    Ückert S, Hedlund P, Waldkirch ES, Sohn M, Jonas U, Andersson KE et al. Interactions between cGMP- and cAMP-pathways are involved in the regulation of penile smooth muscle tone. World J Urol 2004; 22: 261–266.

    Article  Google Scholar 

  24. 24

    Waldkirch ES, Ückert S, Sigl K, Langnaese K, Richter K, Stief CG et al. Expression of cAMP-dependent protein kinase isoforms in the human prostate: functional significance and relation to PDE4. UROLOGY 2010; 76: 515e8–e14.

    Article  Google Scholar 

  25. 25

    Kim NN, Min K, Pessina MA, Munarriz R, Goldstein I, Traish AM . Effects of ovariectomy and steroid hormones on vaginal smooth muscle contractility. Int J Impot Res 2004; 16: 43–50.

    CAS  Article  Google Scholar 

Download references

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Correspondence to S Ückert.

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Ückert, S., Sonnenberg, J., Sonnenberg, J. et al. Protein kinase enzymes in the human vagina—relation to key mediators of the cyclic AMP and cyclic GMP pathways. Int J Impot Res 29, 127–131 (2017). https://doi.org/10.1038/ijir.2017.8

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