Skip to main content
SpringerLink
Log in

5-HT Receptors and KV Channel Internalization

  • Conference paper
  • First Online:
Membrane Receptors, Channels and Transporters in Pulmonary Circulation

Part of the book series: Advances in Experimental Medicine and Biology ((volume 661))

Abstract

Serotonin (5-HT) and voltage-gated potassium (KV) channels have emerged as two major factors in the pathogenesis of pulmonary arterial hypertension (PAH). In pulmonary artery smooth muscle cells (PASMC), KV channels play a major role in the regulation of pulmonary arterial tone and proliferation. Thus, activation of KV channels leads to vasodilatation and enhances apoptosis, while their inhibition is associated with vasoconstriction and proliferation in PASMC. Moreover, these channels have a prominent role as a common target for pulmonary vasoconstrictors. Modulation of these channels by vasoconstrictors involves the activation of a variety of protein kinases. Here we review the role of localization and internalization as a novel mechanism for acute regulation of KV channels and pulmonary vascular tone by agonists such as serotonin.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Humbert M, Morrell NW, Archer SL et al (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43:13S-24S

    Article  PubMed  CAS  Google Scholar 

  2. Yuan JX-J, Rubin LJ (2005) Pathogenesis of pulmonary arterial hypertension. Circulation 111:534-538

    Article  PubMed  Google Scholar 

  3. Long L, MacLean MR, Jeffery TK et al (2006) Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 98:818-827

    Article  PubMed  CAS  Google Scholar 

  4. Fantozzi I, Platoshyn O, Wong AH et al (2006) Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K+ channels in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 291:L993-L1004

    Article  PubMed  CAS  Google Scholar 

  5. Atanassoff PG Weiss BM Schmid ER Tornic M (1992) Pulmonary hypertension and dexfenfluramine Lancet 339:436

    Article  PubMed  CAS  Google Scholar 

  6. Dempsie Y, MacLean MR (2008) Pulmonary hypertension: therapeutic targets within the serotonin system. Br J Pharmacol 155:455-462

    Article  PubMed  CAS  Google Scholar 

  7. Launay JM, Hervé P, Peoch K et al (2002) Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med 8:1129-1135

    Article  PubMed  CAS  Google Scholar 

  8. Hervé P, Launay JM, Scrobohaci ML et al (1995) Increased plasma serotonin in primary pulmonary hypertension. Am J Med 99:249-254

    Article  PubMed  Google Scholar 

  9. Eddahibi S, Humbert M, Fadel E et al. (2001) Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 108:1141-1150

    PubMed  CAS  Google Scholar 

  10. Sullivan CC, Du L, Chu D et al (2003) Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc Natl Acad Sci U S A 100:12331-12336

    Article  PubMed  CAS  Google Scholar 

  11. Eddahibi S, Hanoun N, Lanfumey L et al (2000) Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 105:1555-1562

    Article  PubMed  CAS  Google Scholar 

  12. Keegan A, Morecroft I, Smillie D, Hicks MN, MacLean MR (2001) Contribution of the 5-HT1B receptor to hypoxia-induced pulmonary hypertension: converging evidence using 5-HT1B-receptor knockout mice and the 5-HT1B/1D-receptor antagonist GR127935. Circ Res 89:1231-1239

    Article  PubMed  CAS  Google Scholar 

  13. Guignabert C, Raffestin B, Benferhat R et al (2005) Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation 111:2812-2819

    Article  PubMed  CAS  Google Scholar 

  14. Hironaka E, Hongo M, Sakai A et al (2003) Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Cardiovasc Res 60:692-699

    Article  PubMed  CAS  Google Scholar 

  15. Yuan X-J (1995) Voltage-gated K+ currents regulate resting membrane potential and [Ca2+]i in pulmonary arterial myocytes. Circ Res 77:370-378

    Article  PubMed  CAS  Google Scholar 

  16. Archer S, Souil E, Dinh-Xuan AT et al (1998) Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv1.2, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes. J Clin Invest 101:2319-2330

    Article  PubMed  CAS  Google Scholar 

  17. Burg ED, Remillard CV, Yuan JX-J (2008) Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis: pharmacotherapeutic implications. Br J Pharmacol 153(Suppl 1):S99-S111

    PubMed  CAS  Google Scholar 

  18. Gurney AM, Osipenko ON, MacMillan D, McFarlane KM, Tate RJ, Kempsill FE (2003) Two-pore domain K channel, TASK-1, in pulmonary artery smooth muscle cells. Circ Res 93:957-964

    Article  PubMed  CAS  Google Scholar 

  19. Platoshyn O, Remillard CV, Fantozzi I et al (2004) Diversity of voltage-dependent K+ channels in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 287:L226-L238

    Article  PubMed  CAS  Google Scholar 

  20. Coppock EA, Martens JR, Tamkun MM (2001) Molecular basis of hypoxia-induced pulmonary vasoconstriction: role of voltage-gated K+ channels. Am J Physiol Lung Cell Mol Physiol 281:L1-L12

    PubMed  CAS  Google Scholar 

  21. McMurtry MS, Bonnet S, Wu X et al (2004) Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95:830-840

    Article  PubMed  CAS  Google Scholar 

  22. Yuan X-J Wang J Juhaszova M Gaine SP Rubin L (1998) Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet 351:726-727

    Article  PubMed  CAS  Google Scholar 

  23. Pozeg ZI, Michelakis ED, McMurtry MS et al (2003) In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation 107:2037-2044

    Article  PubMed  CAS  Google Scholar 

  24. McMurtry MS, Archer SL, Altieri DC et al (2005) Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 115:1479-1491

    Article  PubMed  CAS  Google Scholar 

  25. Archer SL, Huang J, Henry T, Peterson D, Weir EK (1993) A redox-based O2 sensor in rat pulmonary vasculature. Circ Res 73:1100-1112

    Article  PubMed  CAS  Google Scholar 

  26. Shimoda LA, Sylvester JT, Sham JSK (1998) Inhibition of voltage-gated K+ current in intrapulmonary arterial myocytes by endothelin-1. Am J Physiol 274:L842-L843

    PubMed  CAS  Google Scholar 

  27. Cogolludo A, Moreno L, Boscá L, Tamargo J, Pérez-Vizcaino F (2003) Thromboxane A2-induced inhibition of voltage-gated K+ channels and pulmonary vasoconstriction. Role of protein kinase Cζ. Circ Res 93:656-663

    Article  PubMed  CAS  Google Scholar 

  28. Cogolludo A, Moreno L, Lodi F, Tamargo J, Perez-Vizcaino F (2005) Postnatal maturational shift from PKCζ and voltage-gated K+ channels to RhoA/Rho kinase in pulmonary vasoconstriction. Cardiovasc Res 66:84-93

    Article  PubMed  CAS  Google Scholar 

  29. Cogolludo A, Moreno L, Lodi F et al (2006) Serotonin inhibits voltage-gated K+ currents in pulmonary artery smooth muscle cells: role of 5-HT2A receptors, caveolin-1, and Kv1.5 channel internalization. Circ Res 98:931-938

    Article  PubMed  CAS  Google Scholar 

  30. Wang J, Juhaszova M, Conte JV, Gaine SP, Rubin LJ, Yuan JX-J (1998) Action of fenfluramine on voltage-gated K+ channels in human pulmonary artery smooth-muscle cells. Lancet 352:290

    Article  PubMed  CAS  Google Scholar 

  31. Hong Z, Smith AJ, Archer SL et al (2005) Pergolide is an inhibitor of voltage-gated potassium channels, including Kv1.5, and causes pulmonary vasoconstriction. Circulation 112:1494-1499

    Article  PubMed  Google Scholar 

  32. Michelakis ED, Thébaud B, Weir EK, Archer SL (2004) Hypoxic pulmonary vasoconstriction: redox regulation of O2-sensitive K+ channels by a mitochondrial O2-sensor in resistance artery smooth muscle cells. J Mol Cell Cardiol 37:1119-1136

    PubMed  CAS  Google Scholar 

  33. Cogolludo A, Frazziano G, Cobeño L et al (2006) Role of reactive oxygen species in Kv channel inhibition and vasoconstriction induced by TP receptor activation in rat pulmonary arteries. Ann N Y Acad Sci 1091:41-51

    Article  PubMed  CAS  Google Scholar 

  34. Moreno L, Frazziano G, Cogolludo A, Cobeño L, Tamargo J, Perez-Vizcaino F (2007) Role of protein kinase Czeta and its adaptor protein p62 in voltage-gated potassium channel modulation in pulmonary arteries. Mol Pharmacol 72:1301-1309

    Article  PubMed  CAS  Google Scholar 

  35. Talley EM, Lei Q, Sirois JE, Bayliss DA (2000) TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron 25:399-410

    Article  PubMed  CAS  Google Scholar 

  36. Tamir H, Hsiung SC, Yu PY et al (1992) Serotonergic signalling between thyroid cells: protein kinase C and 5-HT2 receptors in the secretion and action of serotonin. Synapse 12:155-168

    Article  PubMed  CAS  Google Scholar 

  37. Moscat J, Diaz-Meco MT (2000) The atypical protein kinase Cs. Functional specificity mediated by specific protein adapters. EMBO Rep 1:399-403

    Article  PubMed  CAS  Google Scholar 

  38. Gong J, Xu J, Bezanilla M, van Huizen R, Derin R, Li M (1999) Differential stimulation of PKC phosphorylation of potassium channels by ZIP1 and ZIP2. Science 285:1565-1569

    Article  PubMed  CAS  Google Scholar 

  39. Kim Y, Uhm DY, Shin J, Chung S (2004) Modulation of delayed rectifier potassium channel by protein kinase C zeta-containing signaling complex in pheochromocytoma cells. Neuroscience 125:359-368

    Article  PubMed  CAS  Google Scholar 

  40. Shaul PW, Anderson RG (1998) Role of plasmalemmal caveolae in signal transduction. Am J Physiol 275:L843-L851

    PubMed  CAS  Google Scholar 

  41. Martens JR, Sakamoto N, Sullivan SA, Grobaski TD, Tamkun MM (2001) Isoform-specific localization of voltage-gated K+ channels to distinct lipid raft populations. Targeting of Kv1.5 to caveolae. J Biol Chem 276:8409-8414

    Article  PubMed  CAS  Google Scholar 

  42. McEwen DP, Li Q, Jackson S, Jenkins PM, Martens JR (2008) Caveolin regulates Kv1.5 trafficking to cholesterol-rich membrane microdomains. Mol Pharmacol 73:678-685

    Article  PubMed  CAS  Google Scholar 

  43. Martínez-Mármol R, Villalonga N, Solé L et al (2008) Multiple Kv1.5 targeting to membrane surface microdomains. Cell Physiol 217:667-673

    Article  Google Scholar 

  44. Allen JA, Yadav PN, Roth BL (2008) Insights into the regulation of 5-HT2A serotonin receptors by scaffolding proteins and kinases. Neuropharmacology 55:961-968

    Article  PubMed  CAS  Google Scholar 

  45. Zhao YY, Liu Y, Stan RV et al (2002) Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proc Natl Acad Sci U S A 99:11375-11380

    Article  PubMed  CAS  Google Scholar 

  46. Huang J, Kaminski PM, Edwards JG et al (2008) Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension. Am J Physiol Lung Cell Mol Physiol 294:L1250-L1259

    Article  PubMed  CAS  Google Scholar 

  47. Achcar RO, Demura Y, Rai PR et al (2006) Loss of caveolin and heme oxygenase expression in severe pulmonary hypertension. Chest 129:696-705

    Article  PubMed  CAS  Google Scholar 

  48. Patel HH, Zhang S, Murray F et al (2007) Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension. FASEB J 21:2970-2979

    Article  PubMed  Google Scholar 

  49. Ishiguro M, Morielli AD, Zvarova K, Tranmer BI, Penar PL, Wellman GC (2006) Oxyhemoglobin-induced suppression of voltage-dependent K+ channels in cerebral arteries by enhanced tyrosine kinase activity. Circ Res 99:1252-1260

    Article  PubMed  CAS  Google Scholar 

  50. Bhattacharya S, Puri S, Miledi R, Panicker MM (2002) Internalization and recycling of 5-HT2A receptors activated by serotonin and protein kinase C-mediated mechanisms. Proc Natl Acad Sci U S A 99:14470-14475

    Article  Google Scholar 

Download references

Acknowledgments

Our research is funded by the Spanish Ministerio de Ciencia e Innovación (research grants SAF2005-03770, SAF2008-03948 and AGL2007-66108 to F.P.-V.) and by Fundación Mutua Madrileña (to A.C.).

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Ciber Enfermedades Respiratorias (CIBERES), 28040, Madrid, Spain

    Angel Cogolludo & Francisco Perez-Vizcaino

Authors
  1. Angel Cogolludo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francisco Perez-Vizcaino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angel Cogolludo .

Editor information

Editors and Affiliations

  1. Departments of Medicine and Pharmacology, University of Illinois at Chicago, Chicago, 60612, USA

    Jason X. -J. Yuan

  2. Guy’s Hospital Campus, Dept. Physiology, King’s College London, London, SE1 1UL, United Kingdom

    Jeremy P. T. Ward

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Humana Press, a part of Springer Science+Business Media, LLC

About this paper

Cite this paper

Cogolludo, A., Perez-Vizcaino, F. (2010). 5-HT Receptors and KV Channel Internalization. In: Yuan, JJ., Ward, J. (eds) Membrane Receptors, Channels and Transporters in Pulmonary Circulation. Advances in Experimental Medicine and Biology, vol 661. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-500-2_25

Download citation

Publish with us

Policies and ethics

Search

Navigation