Skip to main content
SpringerLink
Log in

María Teresa Miras Portugal: a pioneer for vesicular nucleotide storage

  • Review Article
  • Published:
Purinergic Signalling Aims and scope Submit manuscript

Abstract

Chromaffin granules are secretory granules present in adrenal medulla chromaffin cells. They contain high contents of catecholamines and nucleotides and have been regarded as a model system for the study of vesicular transmitter uptake and release. In 1988, Dr. María Teresa Miras Portugal, when studying catecholamine biosynthesis, detected a novel group of nucleotides, the diadenosine polyphosphates, in the adrenal chromaffin granules. Based on this finding, she unraveled the existence of diadenosine polyphosphate-mediated chemical transmission, leading to a paradigm shift in the field of purinergic signaling. She is also a pioneer in the studies on vesicular nucleotide storage. First, María Teresa and her group characterized nucleotide transport in chromaffin granules and synaptic vesicles using fluorescent nucleotide derivatives such as 1, N6-ethenoadenosine triphosphates. Then, they revealed the presence of a hypothetical vesicular nucleotide transporter with unique properties in terms of substrate specificity. In this article, we will describe her contributions to vesicular nucleotide storage and the foundations she laid for future studies.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ohkuma S, Moriyama Y, Takano T (1982) Identification and characterization of a proton pump on lysosomes by fluorescein isothiocyanate-dextran fluorescence. Proc Natl Acad Sci USA 79:2758–2762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Moriyama Y, Nelson N (1987) The purified ATPase from chromaffin granules is an anion-dependent proton pump. J Biol Chem 262:9175–9180

    Article  CAS  PubMed  Google Scholar 

  3. Moriyama Y, Nelson N (1987) Nucleotide-binding sites and chemical modification of the chromaffin granule proton ATPase. J Biol Chem 262:14723–10729

    Article  CAS  PubMed  Google Scholar 

  4. Mandel M, Moriyama Y, Hulmes JD, Pan YC, Nelson H, Nelson N (1988) cDNA sequence encoding the 16kDa proteolipid of chromaffin granule implies gene duplication in the evolution of H+-ATPases. Proc Natl Acad Sci USA 85:5521–5524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Moriyama Y, Nelson N (1989) Cold inactivation of vacuolar proton-ATPases. J Biol Chem 264:3577–3582

    Article  CAS  PubMed  Google Scholar 

  6. Sawada K, Echigo N, Juge N, Otsuka M, Omote H, Yamamoto A, Moriyama Y (2008) Identification of a vesicular nucleotide transporter. Proc Natl Acad Sci USA 105:5683–5686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Miras Portugal MT, Gualix J, Pintor J (1998) The neurotransmitter role of diadenosine polyphosphates. FEBS Lett 430:78–82

    Article  CAS  PubMed  Google Scholar 

  8. Delicado EG, Miras Portugal MT, Carrasquero LMG, Leon D, Perez-Sen R, Gualix J (2006) Dinucloside polyphosphates and their interaction with other nucleotide signaling pathways. Pflugers Arch 452:563–572

    Article  CAS  PubMed  Google Scholar 

  9. Miras Portugal MT, Gualix J (2021) Geoffrey Burnstock, our friend and magister: the diadenosine polyphosphate connection. Purinergic Signaling 17:79–84

    Article  CAS  Google Scholar 

  10. Miras Portugal MT, Menéndez-Méndez A, Gómez-Villafuertes R, Ortega F, Delicado EG, Pérez-Sen R, Gualix J (2019) Physiopathological role of the vesicular nucleotide transporter (VNUT) in the central nervous system: relevance of the vesicular nucleotide release as a potential therapeutic target. Front Cell Neurosci 13:224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Menéndez-Méndez A, Diaz-Hernandez JI, Ortega F, Delicado EG, Pérez-Sen R, Gualix J, Gómez-Villafuertes R, Miras Portugal MT (2017) Specific temporal distribution and subcellular localization of a functional vesicular nucleotide transporter (VNUT) in cerebellar granule neurons. Frontier Pharmacol 8:951

    Article  Google Scholar 

  12. Braschko H, Welch AD (1953) Localization of adrenaline in cytoplasmic particles of the bovine adrenal medulla. Naunyn-Schmiedebergs Arch Expt Path Pharmacol 219:17–22

    Google Scholar 

  13. Hillarp NA, Lagerstedt S, Nilson B (1953) The isolation of a granular fraction from the suprarenal medulla, containing the sympathomimetic catechol amines. Acta Physiol Scand 29:251–263

    Article  CAS  PubMed  Google Scholar 

  14. Sjostrand FS, Wetzstein R (1956) Electron microscopic research of the pheochrome (chromaffin) granula in the cells of the adrenal medulla. Experientia 12:196–199

    CAS  PubMed  Google Scholar 

  15. Hillarp NA, Nilson B, Hogberg B (1955) Adenosine triphosphate in the adrenal medulla of the cow. Nature 176:1032–1033

    Article  CAS  PubMed  Google Scholar 

  16. Braschko H, Hagen JM, Hagen P (1957) Mitochondrial enzymes and chromaffin granules. J Physiol 138:316–322

    Article  Google Scholar 

  17. Van Dyke K, Robinson R, Urquilla P, Smith D, Tayler M, Trush M, Wilson M (1977) An analysis of nucleotides and catecholamines in bovine medullary granules by anion exchange high-pressure liquid chromatography and fluorescence. Pharmacology 15:377–391

    Article  PubMed  Google Scholar 

  18. Zimmermann H (1994) Signaling via ATP in the nervous system. Trends Neurosci 17:420–426

    Article  CAS  PubMed  Google Scholar 

  19. Zimmermann H (2008) ATP and acetylcholine, equal brethren. Neurochem Int 52:634–648

    Article  CAS  PubMed  Google Scholar 

  20. Mutafova-Yambolieva VN, Durnin L (2014) The purinergic neurotransmitter revisited: a single substance or multiple players? Pharmacol Ther 144:162–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Njus D, Kelley PM, Harnadek GJ (1986) Bioenergetics of secretory vesicles. Biochim Biophys Acta 853:237–265

    Article  CAS  PubMed  Google Scholar 

  22. Johnson RG (1988) Accumulation of biological amines into chromaffin granules: a model for hormone and neurotransmitter transport. Physiol Rev 68:232–307

    Article  CAS  PubMed  Google Scholar 

  23. Borges R (2013) The ATP or the natural history of neurotransmission. Purinergic Signaling 9:5–6

    Article  CAS  Google Scholar 

  24. Estéves-Herrera J, González-Santana A, Baz-Dávila R, Machado JD, Borges R (2016) The intravesicular cocktail and its role in the regulation of exocytosis. J Neurochem 137:897–903

    Article  Google Scholar 

  25. Estévez-Herrera J, Dominguez N, Pardo MR, González-Santana A, Westhead EW, Borges R, Machado JD (2016) ATP: the crucial component of secretory vesicles. Proc Natl Acad Sci USA 113:E4098-4106

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhang Q, Liu B, Wu Q, Liu B, Li Y, Sun S, Wang Y, Wu X, Chai Z, Jiang X, Liu X, Hu M, Wang Y, Yang Y, Wang L, Kang X, Xiong Y, Zhou Y, Chen X, Zheng L, Zhang B, Wang C, Zhu F, Zhou Z (2019) Differential co-release of two neurotransmitters from a vesicle fusion pore in mammalian adrenal chromaffin cells. Neuron 102:173–183

    Article  CAS  PubMed  Google Scholar 

  27. Zamecnik PC, Stephenson ML, Janeway CM, Randerath K (1966) Enzymatic synthesis of diadenosine tetraphosphate and diadenosine triphosphate with a purified lysyl-sRNA synthase. Biochem Biophys Res Commun 24:91–97

    Article  CAS  PubMed  Google Scholar 

  28. Lüthje H, Ogilvie A (1983) The presence of diadenosine 5’,5’’’-P1-P3-triphosphate in human platelets. Biochem Biophys Res Commun 115:253–260

    Article  PubMed  Google Scholar 

  29. Rodriguez Del Castillo A, Torres M, Delicado EG, Miras Portugal MT (1988) Subcellular distribution studies of diadenosine polyphosphates—Ap4A and Ap5A—in bovine adrenal medulla: presence in chromaffin granules. J Neurochem 51:1696–1703

    Article  CAS  PubMed  Google Scholar 

  30. Pintor J, Kowalewski HJ, Torres M, Miras Portugal MT, Zimmermann H (1992) Synaptic vesicle storage of diadenosine polyphosphates in the Torpedo Electric Organ. Neurosci Res Commun 10:9–15

    CAS  Google Scholar 

  31. Omote H, Moriyama Y (2013) Vesicular neurotransmitter transporters: an approach for studying transporters with purified proteins. Physiology 28:39–50

    Article  CAS  PubMed  Google Scholar 

  32. Stjärne L, Hedqvist R, Lagercrantz H (1970) Catecholamines and adenine nucleotide material in effluent from stimulated adrenal medulla spleen: a study of the exocytosis hypothesis for hormone secretion and neurotransmitter release. Biochem Pharmacol 19:1147–1158

    Article  Google Scholar 

  33. Stevens P, Robinson RL, Van Dyke K, Stitzel R (1972) Studies on the synthesis and release of adenosine triphosphate-8-3H in the isolated perfused cat adrenal gland. J Pharmacol Exp Ther 181:463–471

    CAS  PubMed  Google Scholar 

  34. Winkler H, Schöpf JAL, Hortnagl H, Hörtnagl H (1972) Bovine adrenal medulla: subcellular distribution of newly synthesized catecholamines, nucleotides, and chromogranins. Naunyn-Schmiedebergs Arch Pharmacol 273:43–61

    Article  CAS  PubMed  Google Scholar 

  35. Winkler H, Carmichael SW (1982) Chromaffin granules. In the secretory granule. pp. 3–79. Eds Poisner AM, Trifaró JM, Elsevier Biomedical.

  36. Moriyama Y, Hiasa M, Sakamoto S, Omote H, Nomura M (2017) Vesicular nucleotide transporter (VNUT): the appearance of an actress on the stage of purinergic signaling. Purinergic Signaling 13:387–404

    Article  CAS  Google Scholar 

  37. Hasuzawa N, Moriyama S, Moriyama Y, Nomura M (2020) Physiopathological roles of vesicular nucleotide transporter (VNUT), an essential component for vesicular ATP release. Biochim Biophys Acta Biomembr 1862:183408

    Article  CAS  PubMed  Google Scholar 

  38. Gualix J, Abal M, Pintor J, Garsco-Carmona F, Miras Portugal MT (1996) Nucleotide vesicular transporter of bovine chromaffin granules: evidence for a mnemonic regulation. J Biol Chem 271:1957–1965

    Article  CAS  PubMed  Google Scholar 

  39. Bankston LA, Guidotti G (1996) Characterization of ATP transport into chromaffin granule ghosts. Synergy of ATP and serotonin accumulation in chromaffin granule ghosts. J Biol Chem 271:17132–17138

    Article  CAS  PubMed  Google Scholar 

  40. Johnson RG, Scarpa A (1978) Internal pH of isolated chromaffin vesicles. J Biol Chem 251:2189–2191

    Article  Google Scholar 

  41. Salama G, Johnson RG, Scarpa A (1980) Spectrophotometric measurement of transmembrane potential and pH gradients in chromaffin granules. J Gen Physiol 75:109–140

    Article  CAS  PubMed  Google Scholar 

  42. Gualix J, Pintor J, Miras Portugal MT (1999) Characterization of nucleotide transport into rat brain synaptic vesicles. J Neurochem 73:1098–1104

    Article  CAS  PubMed  Google Scholar 

  43. Roseth S, Fykse EM, Fonnum F (1995) Uptake of L-glutamate into rat brain synaptic vesicles: effect of inhibitors that bind specifically to the glutamate transporter. J Neurochem 65:96–103

    Article  CAS  PubMed  Google Scholar 

  44. Sorensen CE, Novak I (2001) Visualization of ATP release in pancreatic acini in response to cholinergic stimulus. J Biol Chem 276:32925–32932

    Article  CAS  PubMed  Google Scholar 

  45. Gualix J, Fideu MD, Pintor J, Rotllán P, Garcia-Carmona F, Miras Portugal MT (1997) Characterization of diadenosine polyphosphate transport into chromaffin granules from the adrenal medulla. FASEB J 11:981–990

    Article  CAS  PubMed  Google Scholar 

  46. Pietrancosta N, Djibo M, Daumas S, Mestikawy SE, Erickson JD (2020) Molecular, structural, functional, and pharmacological sites for vesicular glutamate transporter regulation. Mol Neurobiol 57:3118–3142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Eriksen J, Li F, Edwards RH (2020) The mechanism and regulation of vesicular glutamate transporter: coordination with the synaptic vesicle cycle. Biochim Biophys Acta 1862:183259

    Article  CAS  Google Scholar 

  48. Gualix J, Abal M, Pintor J, Miras Portugal MT (1996) Presence of ε–adenosine tetraphosphate in chromaffin granules after transport of ε-ATP. FEBS Lett 391:195–198

    Article  CAS  PubMed  Google Scholar 

  49. Taugner G, Wunderlich I (1981) Phosphoryl group transfer by a fraction of the soluble proteins of catecholamine storage vesicles. J Neurochem 36:1879–1892

    Article  CAS  PubMed  Google Scholar 

  50. Mutafova-Yambolieva VN, Hwang SJ, Hao X, Chen H, Zhu MX, Wood JD, Ward SM, Sanders KM (2007) β-Nicotinamide adenine dinucleotide is an inhibitory neurotransmitter in visceral smooth muscle. Proc Natl Acad Sci USA 104:16359–16364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yamboliv IA, Smyth LM, Durnin L, Dai Y, Mutafova-Yambolieva VN (2009) Storage and secretion of beta-NAD, ATP and dopamine in NGF-differentiated rat pheochromocytoma PC12 cells. Eur J Neurosci 30:756–768

    Article  Google Scholar 

  52. Durbnin L, Sanders KM, Mutafova-Yambolieva VN (2013) Differential release of beta-NAD(+) and ATP upon activation of enteric motor neurons in primate and murine colons. Neurogastroenterol Motil 25:e194-2204

    Google Scholar 

  53. Schlüter H, Groβ I, Bachmann J, Kaufmann R, van der Giet M, Tepel M, Nofer JR, Assmann G, Karas M, Jankowski J, Zidek W (1998) Adenosine(5’) oligophospho-(5’) guanosines and guanosine(5’) oligophospho-(5’) guanosines in human platelets. J Clin Invest 101:682–688

    Article  PubMed  PubMed Central  Google Scholar 

  54. Angelova PR, Iversen KZ, Teschemacher AG, Kasparov S, Gourine AV, Abramov AY (2018) Signal transduction in astrocytes: localization and release of inorganic polyphosphate. Glia 66:2126–2136

    Article  PubMed  PubMed Central  Google Scholar 

  55. Müller F, Mutch NJ, Schenk WA, Smith SA, Esterl L, Spronk HM, Schmidbauer S, Gahl WA, Morrissey JH, Renne T (2009) Platelet polyphosphate are proinflammatory and procoagulant mediators in vivo. Cell 139:1143–1156

    Article  PubMed  PubMed Central  Google Scholar 

  56. Pintor J, Gualix J, Miras Portugal MT (1997) Diinosine polyphosphate, a group of dinucleotides with antagonistic effects of diadenosine polyphosphate receptor. Mol Pharmacol 51:177–184

    Article  Google Scholar 

Download references

Acknowledgements

We thank Dr. Aida Menéndez-Méndez and Prof. Herbert Zimmermann for critically reading the manuscript.

Funding

This work was partly supported by the Japanese Society for the Promotion of Science (JSPS) KAKENHI (M. Nomura, Grant Number 26461383; N. Hasuzawa, Grant Number, 21K17653; Y. Moriyama, Grant Number 25253008).

Author information

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 830-0011, Japan

    Yoshinori Moriyama, Nao Hasuzawa & Masatoshi Nomura

Authors
  1. Yoshinori Moriyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nao Hasuzawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masatoshi Nomura
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contribute to the article.

YM is a corresponding author.

moriyama_yoshinori@med.kurume-u.ac.jp.

Corresponding author

Correspondence to Yoshinori Moriyama.

Ethics declarations

Ethics approval

This article does not contain any studies with human participants or animals performed by the authors.

Conflict of interest

The authors declare no competing interests.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moriyama, Y., Hasuzawa, N. & Nomura, M. María Teresa Miras Portugal: a pioneer for vesicular nucleotide storage. Purinergic Signalling 20, 93–98 (2024). https://doi.org/10.1007/s11302-022-09912-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11302-022-09912-z

Keywords

Search

Navigation