Skip to main content
Log in

The role of ion antiporters in the maintenance of intracellular pH in rat vascular smooth muscle cells

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Vascular smooth muscle intracellular pH is maintained by the Na+/H+ and Cl/HCO 3 antiporters. The Na+/H+ exchanger is a major route of H+ extrusion in most eukaryotic cells and is present in vascular smooth muscle cells in a similar capacity. It extrudes H into the extracellular space in exchange for Na+. The Cl/HCO 3 exchanger plays an analogous role to lower the pH of vascular smooth muscle cells when increases in intracellular pH occur. Its activity has also been demonstrated in A7r5 and A10 vascular smooth muscle cells. The Na+/H+ exchanger is regulated by a number of agents which act through inositol trisphosphate/diacylglycerol, to stimulate the antiporter. Calcium-calmodulin dependent protein kinase may also activate the antiporter in vivo. Phosphorylation of the Cl/HCO 3 exchanger has also been observed but its physiological role is not known. Both these antiporters exist in the plasma membrane as integral proteins with free acidic cytoplasmic termini. These regions may be important in ‘sensing’ changes in intracellular pH, to which these antiporters respond.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

CaM:

Calmodulin

DCCD:

Dicylohexyl-Carbodiimide

DG:

Diacylglycerol

DIDS-4:

4′-Diisthiocyanostilbene-2,2′-Disulfonic Acid

IP3 :

Inositol Trisphosphate

PKC:

protein Kinase C

SITS-4:

4-Acetamido-4-Isothiocyanstilbene-2,2′-Disulfonate

VSMC:

Vascular Smooth Muscle Cell

References

  1. Hoffmann E, Simonsen LO: Membrane mechanisms in volume and pH regulation in vertebrate cells. Physiol Rev 69:315–382, 1989

    CAS  PubMed  Google Scholar 

  2. Nucitelli R, Webb DJ, Lagier ST, Matson GB: 31PNMR reveals increased intracellular pH after fertilization in Xenopus eggs. Proc Natl Acad Sci USA 78: 4421–4425, 1981

    Google Scholar 

  3. Hesketh TR, Moore JP, Morris JDH, Taylor MV, Rogers J, Smith GA, Metcalfe JC: A common sequence of calcium and pH signals in the mitogenic stimulation of eukaryotic cells. Nature 313: 481–484, 1985

    Google Scholar 

  4. Berk B, Canessa M, Vallega G, Alexander R: J Cardiovasc Pharmacol 12 Suppl 5: S104, 1988

    Google Scholar 

  5. Berk BC, Brock TA, Gimborne MA Jr, Alexander RW: Early agonist-mediated ionic events in cultured vascular smooth muscle cells. J Biol Chem 262: 5065–5072, 1987

    Google Scholar 

  6. Vigne P, Breittmayer JP, Frelin C, Lazdunski M: Dual control of the intracellular pH in aortic smooth muscle cells by a cAMP-sensitive Cl/HCO 3 antiporter and a protein kinase C-sensitive Na+/H+ antiporter. J Biol Chem 263: 18023–18029, 1988

    Google Scholar 

  7. Korbmacher C, Helbig H, Stahl F, Wiederhold M: Evidence for Na+/H+ exchange and Cl/HCO 3 exchange in A10 vascular smooth muscle cells. Pflugers Arch 412: 29–36, 1988

    Google Scholar 

  8. O'Donnell ME, Owen NE: Role of cyclic GMP in atrial natriuretic factor stimulation of Na+, K+, Cl cotransport in vascular smooth muscle cells. J Biol Chem 261: 15461–15466, 1986

    Google Scholar 

  9. Frohlich O: Antiporters. Current Opinion in Cell Biol 1: 729–734, 1989

    Google Scholar 

  10. Hatori N, Fine BP, Nakamura A, Cragoe E Jr, Aviv A: Angiotensin II effect on cytosolic pH in cultured rat vascular smooth muscle cells. J Biol Chem 262: 5073–5078, 1987

    Google Scholar 

  11. Berk BC, Aronow MS, Brock TA, Cragoe EJ Jr, Gimborne MA Jr, Alexander RW: Angiotensin II-stimulated Na+/H+ exchange in cultured vascular smooth muscle cells. J Biol Chem 262: 5057–5064, 1987

    Google Scholar 

  12. Little PJ, Cragoe EJ Jr, Bobik A: Na+/H+ exchange is a major pathway for Na influx in rat vascular smooth muscle. Am J Physiol 251: C707-C712, 1986

    Google Scholar 

  13. Weissberg PL, Little PJ, Cragoe EJ Jr, Bobik A: Na+/H+ antiport in cultured rat aortic smooth muscle: its role in cytoplasmic pH regulation. Am J Physiol 253: C193-C198, 1987

    Google Scholar 

  14. Mitsuhashi T, Ives HE: Intracellular Ca2+ requirement for activation of the Na+/H+ exchanger in vascular smooth muscle cells. J Biol Chem 263: 8790–8795, 1988

    Google Scholar 

  15. Kleyman TR, Cragoe EJ Jr: Amiloride and its analogues as tools in the study of ion transport. J Mem Biol 105: 1–21, 1988

    Google Scholar 

  16. Kahn AM, Shelat H, Allen JC: Na+/H+ exchange is present in sarcolemmal vesicles from dog superior mesenteric artery. Am J Physiol 250: H313-H319, 1986

    Google Scholar 

  17. Kahn AM, Allen JC, Cragoe EJ Jr, Shelat H: Sodium-lithium and sodium proton exchange are mediated by the same transport system in sarcolemma vesicles from bovine superior mesenteric artery. Circ Res 65: 818–828, 1989

    Google Scholar 

  18. Aronson PS, Igarashi P: Molecular properties and physiological roles of the renal Na+/H+ exchanger. In: PS Aronson and WF Boron (eds.) Na+/H+ Exchange, Intracellular pH and Cell Function. Current Topics in Membranes and Transport, Academic Press, New York 1986, Vol 26 pp 57–75

    Google Scholar 

  19. Janas T, Bjerrum PJ, Brahm J, Wieth JO: Kinetics of reversible DIDS inhibition of chloride self exchange in human erythrocytes. Am J Physiol 257: C601-C606, 1989

    Google Scholar 

  20. Cassel D, Scharf O, Rotman M, Cragoe E Jr, Katz M: Characterization of Na+-linked and Na+-independent C/HCO 3 exchange systems in Chinese hamster lung fibroblasts. J Biol Chem 263: 6122–6127, 1988

    Google Scholar 

  21. Korbmacher C, Helbig H, Blank M, Dressler S, Stahl F, Wiederhold M: Characterization of Cl-/HCO t-3 exchange in A10 vascular smooth muscle cells using 36Cl. Biochim Biophys Acta 985: 67–74, 1989

    Google Scholar 

  22. Jay D, Cantley L: Structural aspects of the red anion exchange protein. Ann Rev Biochem 55: 511–538, 1986

    Google Scholar 

  23. Huang C, Cogan MG, Cragoe EJ Jr, Ives HE: Thrombin activation of the Na+/H+ exchanger in vascular smooth muscle cells. J Biol Chem 262: 14134–14140, 1987

    Google Scholar 

  24. Kuriyama S, Nakamura A, Hopp L, Fine BP, Kino M, Cragoe EJ Jr, Aviv A: Angiotensin II effect on 22Na+ transport in vascular smooth muscle cells. J Cardiovasc Pharmacol 11: 139–146, 1988

    Google Scholar 

  25. Berridge MJ: Inositol trisphosphate and diacylglycerol: two interacting second messengers. Ann Rev Biochem 56: 159–193, 1987

    Google Scholar 

  26. Griendling KK, Berk BC, Alexander RW: Evidence that Na+/H+ exchange regulates angiotensin II-stimulated diacylglycerol accumulation in vascular smooth muscle cells. J Biol Chem 236: 10620–10624, 1988

    Google Scholar 

  27. Vallega GA, Canessa ML, Berk BC, Brock TA, Alexander RW: Vascular smooth muscle Na+/H+ exchanger kinetics and its activation by angiotensin II. Am J Physiol 254: C751-C758, 1988

    Google Scholar 

  28. Little PJ, Weissberg PL, Cragoe E Jr, Bobik A: Dependence of Na+/H+ antiport activation in cultured rat aortic smooth muscle on calmodulin, calcium, and ATP. J Biol Chem 263: 16780–16786, 1988

    Google Scholar 

  29. Green J, Muallem S: A common mechanism for activation of the Na+/H+ exchanger by different types of stimuli. FASEB J 3: 2408–2414, 1989

    Google Scholar 

  30. Moolenaar WH, Bierman AJ, deLaat SW: Effect of growth factors on Na+/H+ exchange. In: S Grinstein (ed.) Na+/H+ exchange. CRC Press Inc Boca Raton, FL, 1988, pp 227–234

    Google Scholar 

  31. Sardet C, Counillon L, Franchi A, Pouyssegur J: Growth factors induce phosphorylation of the Na+/H+ antiporter, a glycoprotein of 110 kD. Science 247: 723–725, 1990

    Google Scholar 

  32. Rosoff PM: Phorbol esters and the regulation of Na+/H+ exchange. In: S Grinstein (ed.) Na+/H+ exchange. CRC Press Inc Boca Raton, FL, 1988, pp 235–242

    Google Scholar 

  33. Villerael ML: Regulation of Na+/H+ exchange: Role of Ca2+. In: S Grinstein (ed.) Na+/H+ exchange. CRC Press Inc Boca Raton, FL, 1988, pp 243–253

    Google Scholar 

  34. Low P: Structure and function of the cytoplasmic domain of band 3: center of erythrocyte membrane-peripheral protein interactions. Biochim Biophys Acta 864: 145–167, 1986

    Google Scholar 

  35. Alper SL, Kopito RR, Libresco SM, Lodish HF: Cloning and characterization of a murine band 3-related cDNA from kidney and from a lymphoid cell line. J Biol Chem 263: 17092–17099, 1988

    Google Scholar 

  36. Brosius FC, Alper SL, Gracia AM, Lodish HF: The major kidney band 3 gene transcript predicts an amino-terminal truncated band 3 polypeptide. J Biol Chem 264: 7784–7787, 1989

    Google Scholar 

  37. Kudrycki KE, Schull GE: Primary structure of the rat kidney band 3 anion exchange protein deduced from a cDNA. J Biol Chem 264: 8185–8192, 1989

    Google Scholar 

  38. Demuth D, Showe LC, Ballantine M, Palumbo A, Fraser PJ, Cioe L, Rovera G, Curtis P: Cloning and structural characterization of a human non-erythroid band 3-like protein. EMBO J. 5: 1205–1214, 1986

    Google Scholar 

  39. Hoffmann EK: Anion exchange and anion-cation co-transport systems in mammalian cells. Phill Trans R Soc Lond B299: 519–535, 1982

    Google Scholar 

  40. Cheng S, Levy D: Characterization of the anion transport system in hepatocyte plasma membranes. J Biol Chem 255: 2637–2640, 1980

    Google Scholar 

  41. Kimelberg HK, Biddlecome S, Bourke RS: SITS-inhibitable Cl transport and Na+-dependent H+ production in primary astroglial cultures. Brain Res 173: 111–124, 1979

    Google Scholar 

  42. Schuster VL, Bonsib SM, Jenning ML: Two types of collecting duct mitochondria-rich (intercalated) cells: lectin and band 3 cytochemistry. Am J Physiol 251: C347-C355, 1986

    Google Scholar 

  43. Civan MM, Cragoe EJ Jr, Peterson-Yantorno K: Intracellular pH in frog skin: effects of Na, volume, and cAMP. Am J Physiol 255: F126-F134, 1988

    Google Scholar 

  44. Drenckhahn D, Oelmann M, Schaaf P, Wagner M, Wagner S: Band 3 is the basolateral anion exchanger of dark epithelial cells of turtle urinary bladder. Am J Physiol 252: C570-C574, 1987

    Google Scholar 

  45. Drenckhahn D, Zinke K, Schauer U, Appell KC, Low PS: Identification of immunoreactive forms of human erythrocyte band 3 in nonerythroid cells. Eur J Cell Biol 34: 144–150, 1984

    Google Scholar 

  46. Restrepo D, Kozody DJ, Spinelli LJ, Knauf PA: Cl-Cl exchange in promyelocytic HL-60 cells follows simultaneous rather than ping-pong kinetics. Am J Physiol 257: C520-C527, 1989

    Google Scholar 

  47. Low P, Westfall MA, Allen DP, Appell KC: Characterization of the reversible conformational equilibrium of the cytoplasmic domain of erythrocyte membrane band 3. J Biol Chem 259: 13071–13076, 1984

    Google Scholar 

  48. Kopito RR, Lodish HF: Primary structure and transmembrane orientation of the murine anion exchange protein. Nature 316: 234–238, 1985

    Google Scholar 

  49. Kopito RR, Lee BS, Simmons DM, Lindsey AE, Morgans CW, Schneider K: Regulation of intracellular pH by a neuronal homolog of the erythrocyte anion exchanger. Cell 599: 927–937, 1989

    Google Scholar 

  50. Kudrycki KE, Newman PR, Schull GE: cDNA cloning and tissue distribution of mRNA for two proteins that related to the band 3 Cl/HCO t-3 exchanger. J Biol Chem 265: 462–471, 1990

    Google Scholar 

  51. Wu JSR, Lever JE: Photoaffinity labeling by [3H]-N5-me-thyl-N5-isobutylamiloride of proteins which cofractionate with Na+/H+ antiport activity. Biochemistry 28: 2980–2984, 1989

    Google Scholar 

  52. Sardet C, Franchi A, Pouyssegur J: Molecular cloning, primary structure, and expression of the human growth factor — activatable Na+/H+ antiporter. Cell 56: 271–280, 1989

    Google Scholar 

  53. Engelman DM, Steitz TA, Goldman A: Identifying nonpolar transbilayer helices in amino acid sequences of membrane proteins. Ann Rev Biophys Biochem 15: 321–353, 1986

    Google Scholar 

  54. Sardet C, Franchi A, Pouyssegur J: Molecular cloning of the growth-factor-activatable human Na+/H+ antiporter. Cold Spring Harbor Symposium III: 1011–1018, 1988

    Google Scholar 

  55. Huot S, Cassel D, Igarashi P, Cragoe E, Slayman C, Aronson P: Identification and purification of a renal amiloride-binding protein with properties of the Na+/H+ exchanger. J Biol Chem 264: 683–686, 1989

    Google Scholar 

  56. Igarashi P, Aronson PS: Covalent modification of the renal Na+/H+ exchanger by N,N′-dicyclohexylcarbodiimide. J Biol Chem 262: 860–868, 1987

    Google Scholar 

  57. Friedrich T, Sablotni J, Buckhardt G: Identification of the renal Na+/H+ exchanger with N,N′-dicyclohexylcarbodiimide (DCCD) and amiloride analogues. J Mem Biol 94: 253–266, 1986

    Google Scholar 

  58. Haggerty JG, Agarwal N, Reilli RF, Adelberg EA, Slayman CW: Pharmacologically different Na+/H+ antiporters on the apical and basolateral surfaces of cultured porcine kidney cells (LLC-PK1): Proc Natl Acad Sci USA 85: 6796–6801, 1988

    Google Scholar 

  59. Kulanthaivel P, Leibach FH, Mahesh VB, Cragoe ER Jr, Ganapathy V: The Na+/H+ exchange of the placental brush-border membrane is pharmacologically distinct from that of the renal brush border membrane. J Biol Chem 265: 1249–1252, 1990

    Google Scholar 

  60. Casavola V, Helmle-Kolb C, Murer H: Separate regulatory control of apical and basolateral Na+/H+ exchange in renal epithelial cells. Biochem Biophys Res Comm 165: 833–837, 1989

    Google Scholar 

  61. Knickelbein RC, Aronson PS, Dobbins JW: Properties of distinct luminal and basolateral Na:H exchangers in rabbit ileum (Abstr.) FASEB J 2: A941, 1988

  62. Ross W, Bertrand W, Morrison A: A photoactivatable probe for the Na+/H+ exchanger cross links a 66-kDa renal brush border membrane protein. J Biol Chem 265: 5341–5344, 1990

    Google Scholar 

  63. Otsu K, Kinsella J, Sacktor B, Froelich J: Evidence for a functional oligomer in the mechanism of Na+/H+ exchange (Abstr.) Biophys J 53: 341a, 1988

  64. Fliegel L, Burns K, Opas M, Michalak M: The high affinity calcium binding protein of sarcoplasmic reticulum. Tissue distribution and homology with calregulin. Biochim Biophys Acta 982: 1–8, 1989

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hogue, D., Michalak, M. & Fliegel, L. The role of ion antiporters in the maintenance of intracellular pH in rat vascular smooth muscle cells. Mol Cell Biochem 102, 125–137 (1991). https://doi.org/10.1007/BF00234570

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00234570

Key words

Navigation