DOI QR코드

DOI QR Code

Testosterone secretion is affected by receptor tyrosine kinase c-Kit and anoctamin 1 activation in mouse Leydig cells

  • Ko, Eun-A (Department of Physiology, Colledge of Medicine, Jeju National University) ;
  • Woo, Min Seok (Department of Physiology, College of Medicine and Institute of Health Sciences, Gyeongsang National University) ;
  • Kang, Dawon (Department of Physiology, College of Medicine and Institute of Health Sciences, Gyeongsang National University)
  • Received : 2022.05.12
  • Accepted : 2022.05.22
  • Published : 2022.06.30

Abstract

Receptor tyrosine kinase c-Kit, a marker found on interstitial cells of Cajal (ICCs), is expressed in Leydig cells, which are testicular interstitial cells. The expression of other ICC markers has not yet been reported. In this study, we investigated the expression of c-Kit and anoctamin 1 (ANO1), another ICC marker, in mouse testes. In addition, the relationship between c-Kit and ANO1 expression and Leydig cell function was investigated. We observed that c-Kit and ANO1 were predominantly expressed in mouse Leydig cells. The mRNA and protein of c-Kit and ANO1 were expressed in TM3, a mouse Leydig cell line. LH induced an increase in intracellular Ca2+ concentration, membrane depolarization, and testosterone secretion, whereas these signals were inhibited in the presence of c-Kit and ANO1 inhibitors. These results show that c-Kit and ANO1 are expressed in Leydig cells and are involved in testosterone secretion. Our findings suggest that Leydig cells may act as ICCs in testosterone secretion.

Keywords

Acknowledgement

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2021R1I1A3044128).

References

  1. Abdou HS, Villeneuve G, Tremblay JJ. 2013. The calcium signaling pathway regulates leydig cell steroidogenesis through a transcriptional cascade involving the nuclear receptor NR4A1 and the steroidogenic acute regulatory protein. Endocrinology 154:511-520. https://doi.org/10.1210/en.2012-1767
  2. Baker SA, Leigh WA, Del Valle G, De Yturriaga IF, Ward SM, Cobine CA, Drumm BT, Sanders KM. 2021. Ca2+ signaling driving pacemaker activity in submucosal interstitial cells of Cajal in the murine colon. Elife 10:e64099. https://doi.org/10.7554/eLife.64099
  3. Bayguinov O, Ward SM, Kenyon JL, Sanders KM. 2007. Voltage-gated Ca2+ currents are necessary for slow-wave propagation in the canine gastric antrum. Am. J. Physiol. Cell Physiol. 293:C1645-C1659. https://doi.org/10.1152/ajpcell.00165.2007
  4. Chevalier NR, Ammouche Y, Gomis A, Teyssaire C, de Santa Barbara P, Faure S. 2020. Shifting into high gear: how interstitial cells of Cajal change the motility pattern of the developing intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 319:G519-G528. https://doi.org/10.1152/ajpgi.00112.2020
  5. Choi S, Kang HG, Wu MJ, Jiao HY, Shin DH, Hong C, Jun JY. 2018. Effects of Ca2+-activated Cl- channel ANO1inhibitors on pacemaker activity in interstitial cells of Cajal. Cell. Physiol. Biochem. 51:2887-2899. https://doi.org/10.1159/000496041
  6. Choi S, Seo H, Lee K, Shin DH, Wu MJ, Wu W, Huang X, Zhang J, Hong C, Jun JY. 2022. Hyperpolarization-activated cyclic nucleotide-gated channels working as pacemaker channels in colonic interstitial cells of Cajal. J. Cell. Mol. Med. 26:364-374. https://doi.org/10.1111/jcmm.17087
  7. Chung JY, Brown S, Chen H, Liu J, Papadopoulos V, Zirkin B. 2020. Effects of pharmacologically induced Leydig cell testosterone production on intratesticular testosterone and Spermatogenesis. Biol. Reprod. 102:489-498. https://doi.org/10.1093/biolre/ioz174
  8. Costa RR and Varanda WA. 2007. Intracellular calcium changes in mice Leydig cells are dependent on calcium entry through T-type calcium channels. J. Physiol. 585(Pt 2):339-349. https://doi.org/10.1113/jphysiol.2007.137950
  9. Drumm BT, Hannigan KI, Lee JY, Rembetski BE, Baker SA, Koh SD, Cobine CA, Sanders KM. 2022. Ca2+ signalling in interstitial cells of Cajal contributes to generation and maintenance of tone in mouse and monkey lower oesophageal sphincters. J. Physiol. Advanced online publication. doi: 10.1113/JP282570
  10. Drumm BT, Rembetski BE, Huynh K, Nizar A, Baker SA, Sanders KM. 2020. Excitatory cholinergic responses in mouse colon intramuscular interstitial cells of Cajal are due to enhanced Ca2+ release via M3 receptor activation. FASEB J. 34:10073-10095. https://doi.org/10.1096/fj.202000672R
  11. Drumm BT, Thornbury KD, Hollywood MA, Sergeant GP. 2021. Role of Ano1 Ca2+-activated Cl- channels in generating urethral tone. Am. J. Physiol. Renal Physiol. 320:F525-F536. https://doi.org/10.1152/ajprenal.00520.2020
  12. Edling CE and Hallberg B. 2007. c-Kit--a hematopoietic cell essential receptor tyrosine kinase. Int. J. Biochem. Cell Biol. 39:1995-1998. https://doi.org/10.1016/j.biocel.2006.12.005
  13. Feng HL, Sandlow JI, Sparks AE, Sandra A, Zheng LJ. 1999. Decreased expression of the c-kit receptor is associated with increased apoptosis in subfertile human testes. Fertil. Steril. 71:85-89. https://doi.org/10.1016/S0015-0282(98)00401-4
  14. Ge RS, Dong Q, Sottas CM, Chen H, Zirkin BR, Hardy MP. 2005. Gene expression in rat leydig cells during development from the progenitor to adult stage: a cluster analysis. Biol. Reprod. 72:1405-1415. https://doi.org/10.1095/biolreprod.104.037499
  15. Gomez-Pinilla PJ, Gibbons SJ, Bardsley MR, Lorincz A, Pozo MJ, Pasricha PJ, Van de Rijn M, West RB, Sarr MG, Kendrick ML, Cima RR, Dozois EJ, Larson DW, Ordog T, Farrugia G. 2009. Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract. Am. J. Physiol. Gastrointest. Liver Physiol. 296:G1370-G1381. https://doi.org/10.1152/ajpgi.00074.2009
  16. Han D, Kim JN, Kwon MJ, Han T, Kim YT, Kim BJ. 2021. Salvia miltiorrhiza induces depolarization of pacemaker potentials in murine small intestinal interstitial cells of Cajal via extracellular Ca2+ and Na+ influx. Mol. Med. Rep. 23:348. https://doi.org/10.3892/mmr.2021.11987
  17. Hennig GW, Spencer NJ, Jokela-Willis S, Bayguinov PO, Lee HT, Ritchie LA, Ward SM, Smith TK, Sanders KM. 2010. ICC-MY coordinate smooth muscle electrical and mechanical activity in the murine small intestine. Neurogastroenterol. Motil. 22:e138-e151. https://doi.org/10.1111/j.1365-2982.2009.01448.x
  18. Ishida T, Koyanagi-Aoi M, Yamamiya D, Onishi A, Sato K, Uehara K, Fujisawa M, Aoi T. 2021. Differentiation of human induced pluripotent stem cells into testosterone-producing Leydig-like cells. Endocrinology 162:bqab202. https://doi.org/10.1210/endocr/bqab202
  19. Joffre M, Roche A, Duchatelle P. 1988. Electrophysiological studies of the action of gonadotropins on Leydig and Sertoli cells from rat testis. Reprod. Nutr. Dev. 28(4B):1019-1029. https://doi.org/10.1051/rnd:19880703
  20. Liu Q, Huang X, Zhang H, Tian X, He L, Yang R, Yan Y, Wang QD, Gillich A, Zhou B. 2015. c-kit(+) cells adopt vascular endothelial but not epithelial cell fates during lung maintenance and repair. Nat. Med. 21:866-868. https://doi.org/10.1038/nm.3888
  21. Loera-Valencia R, Wang XY, Wright GW, Barajas-Lopez C, Huizinga JD. 2014. Ano1 is a better marker than c-Kit for transcript analysis of single interstitial cells of Cajal in culture. Cell. Mol. Biol. Lett. 19:601-610.
  22. Malysz J, Gibbons SJ, Saravanaperumal SA, Du P, Eisenman ST, Cao C, Oh U, Saur D, Klein S, Ordog T, Farrugia G. 2017. Conditional genetic deletion of Ano1 in interstitial cells of Cajal impairs Ca2+ transients and slow waves in adult mouse small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 312:G228-G245. https://doi.org/10.1152/ajpgi.00363.2016
  23. Ma Y, Chen Y, Zheng Y, Wen Y, Li Y, Feng J, He Y, Wen J. 2020. SCF/c-kit signaling pathway participates in ICC damage in neurogenic bladder. Cell Cycle 19:2074-2080. https://doi.org/10.1080/15384101.2020.1793059
  24. O'Donnell L, Smith LB, Rebourcet D. 2022. Sertoli cells as key drivers of testis function. Semin. Cell Dev. Biol. 121:2-9. https://doi.org/10.1016/j.semcdb.2021.06.016
  25. Parsons SP and Huizinga JD. 2020. A myogenic motor pattern in mice lacking myenteric interstitial cells of Cajal explained by a second coupled oscillator network. Am. J. Physiol. Gastrointest. Liver Physiol. 318:G225-G243. https://doi.org/10.1152/ajpgi.00311.2019
  26. Payne AH and Youngblood GL. 1995. Regulation of expression of steroidogenic enzymes in Leydig cells. Biol. Reprod. 52:217-225. https://doi.org/10.1095/biolreprod52.2.217
  27. Popescu LM, Vidulescu C, Curici A, Caravia L, Simionescu AA, Ciontea SM, Simion S. 2006. Imatinib inhibits spontaneous rhythmic contractions of human uterus and intestine. Eur. J. Pharmacol. 546:177-181. https://doi.org/10.1016/j.ejphar.2006.06.068
  28. Rothschild G, Sottas CM, Kissel H, Agosti V, Manova K, Hardy MP, Besmer P. 2003. A role for kit receptor signaling in Leydig cell steroidogenesis. Biol. Reprod. 69:925-932. https://doi.org/10.1095/biolreprod.102.014548
  29. Sanders KM. 2019. Spontaneous electrical activity and rhythmicity in gastrointestinal smooth muscles. Adv. Exp. Med. Biol. 1124:3-46. https://doi.org/10.1007/978-981-13-5895-1_1
  30. Sanders KM, Koh SD, Ward SM. 2006. Interstitial cells of cajal as pacemakers in the gastrointestinal tract. Annu. Rev. Physiol. 68:307-343. https://doi.org/10.1146/annurev.physiol.68.040504.094718
  31. Sandlow JI, Feng HL, Cohen MB, Sandra A. 1996. Expression of c-KIT and its ligand, stem cell factor, in normal and subfertile human testicular tissue. J. Androl. 17:403-408.
  32. Sferra R, Pompili S, D'Alfonso A, Sabetta G, Gaudio E, Carta G, Festuccia C, Colapietro A, Vetuschi A. 2019. Neurovascular alterations of muscularis propria in the human anterior vaginal wall in pelvic organ prolapse. J. Anat. 235:281-288. https://doi.org/10.1111/joa.13014
  33. Shafik A, Shafik I, el-Sibai O. 2005. Identification of c-kit-positive cells in the human prostate: the interstitial cells of Cajal. Arch. Androl. 51:345-351. https://doi.org/10.1080/014850190944456
  34. Singh RD, Gibbons SJ, Saravanaperumal SA, Du P, Hennig GW, Eisenman ST, Mazzone A, Hayashi Y, Cao C, Stoltz GJ, Ordog T, Rock JR, Harfe BD, Szurszewski JH, Farrugia G. 2014. Ano1, a Ca2+-activated Cl- channel, coordinates contractility in mouse intestine by Ca2+ transient coordination between interstitial cells of Cajal. J. Physiol. 592:4051-4068. https://doi.org/10.1113/jphysiol.2014.277152
  35. Siregar AS, Nyiramana MM, Kim EJ, Shin EJ, Kim CW, Lee DK, Hong SG, Han J, Kang D. 2019. TRPV1 is associated with testicular apoptosis in mice. J. Anim. Reprod. Biotechnol. 34:311-317. https://doi.org/10.12750/JARB.34.4.311
  36. Sullivan MH and Cooke BA. 1986. The role of Ca2+ in steroidogenesis in Leydig cells. Stimulation of intracellular free Ca2+ by lutropin (LH), luliberin (LHRH) agonist and cyclic AMP. Biochem. J. 236:45-51. https://doi.org/10.1042/bj2360045
  37. Tamada H and Kiyama H. 2015. Existence of c-Kit negative cells with ultrastructural features of interstitial cells of Cajal in the subserosal layer of the W/W(v) mutant mouse colon. J. Smooth Muscle Res. 51:1-9. https://doi.org/10.1540/jsmr.51.1
  38. Tong W, Jia H, Zhang L, Li C, Ridolfi TJ, Liu B. 2010. Exogenous stem cell factor improves interstitial cells of Cajal restoration after blockade of c-kit signaling pathway. Scand. J. Gastroenterol. 45:844-851. https://doi.org/10.3109/00365521003782371
  39. Unni SK, Modi DN, Pathak SG, Dhabalia JV, Bhartiya D. 2009. Stage-specific localization and expression of c-kit in the adult human testis. J. Histochem. Cytochem. 57:861-869. https://doi.org/10.1369/jhc.2009.953737
  40. Wang JP, Ding GF, Wang QZ. 2013. Interstitial cells of Cajal mediate excitatory sympathetic neurotransmission in guinea pig prostate. Cell Tissue Res. 352:479-486. https://doi.org/10.1007/s00441-013-1572-3
  41. Ward SM, Baker SA, de Faoite A, Sanders KM. 2003. Propagation of slow waves requires IP3 receptors and mitochondrial Ca2+ uptake in canine colonic muscles. J. Physiol. 549(Pt 1):207-218. https://doi.org/10.1113/jphysiol.2003.040097
  42. Ward SM, Burns AJ, Torihashi S, Harney SC, Sanders KM. 1995. Impaired development of interstitial cells and intestinal electrical rhythmicity in steel mutants. Am. J. Physiol. 269(6 Pt 1):C1577-C1585. https://doi.org/10.1152/ajpcell.1995.269.6.C1577
  43. Wishahi M, Hafiz E, Wishahy AMK, Badawy M. 2021. Telocytes, c-Kit positive cells, Smooth muscles, and collagen in the ureter of pediatric patients with congenital primary obstructive megaureter: elucidation of etiopathology. Ultrastruct. Pathol. 45:257-265. https://doi.org/10.1080/01913123.2021.1954734
  44. Yang JH, Siregar AS, Kim EJ, Nyiramana MM, Shin EJ, Han J, Sohn JT, Kim JW, Kang D. 2019. Involvement of TREK-1 channel in cell viability of H9c2 rat cardiomyoblasts affected by bupivacaine and lipid emulsion. Cells 8:454. https://doi.org/10.3390/cells8050454
  45. Ye L, Li X, Li L, Chen H, Ge RS. 2017. Insights into the development of the adult Leydig cell lineage from stem Leydig cells. Front. Physiol. 8:430.
  46. Zheng H, Drumm BT, Zhu MH, Xie Y, O'Driscoll KE, Baker SA, Perrino BA, Koh SD, Sanders KM. 2020. Na+/Ca2+ exchange and pacemaker activity of interstitial cells of Cajal. Front. Physiol. 11:230. (Erratum published 2020, Front. Physiol. 11:362) https://doi.org/10.3389/fphys.2020.00230
  47. Zirkin BR and Papadopoulos V. 2018. Leydig cells: formation, function, and regulation. Biol. Reprod. 99:101-111. https://doi.org/10.1093/biolre/ioy059