Skip to main content

Advertisement

Springer Nature Link
Log in

Glutamatergic Regulation of Hypothalamic Presympathetic Neurons in Hypertension

  • Hypertension and the Brain (R Wainford, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Elevated sympathetic vasomotor tone emanating from the brain is a major mechanism involved in the development of hypertension. Increased glutamatergic excitatory input to presympathetic neurons in the paraventricular nucleus (PVN) of the hypothalamus leads to increased sympathetic outflow in various animal models of hypertension. Recent studies have revealed molecular and cellular mechanisms underlying enhanced glutamatergic synaptic input to PVN presympathetic neurons in hypertension. In this review article, we summarize recent findings on changes in inotropic and metabotropic glutamate receptors, at both presynaptic and postsynaptic sites, responsible for increased glutamatergic input to PVN presympathetic neurons in hypertension. Particular emphasis is placed on the role of protein kinases and phosphatases in the potentiated activity of synaptic NMDA receptors in the PVN in hypertension. New findings about glutamatergic synaptic plasticity in the PVN not only improve the understanding of molecular mechanisms involved in heightened activity of the sympathetic nervous system but also suggest new therapeutic targets for treating drug-resistant, neurogenic hypertension.

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

Access this article

Log in via an institution

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Allen AM. Inhibition of the hypothalamic paraventricular nucleus in spontaneously hypertensive rats dramatically reduces sympathetic vasomotor tone. Hypertension. 2002;39(2):275–80.

    Article  CAS  PubMed  Google Scholar 

  2. Judy WV, Watanabe AM, Henry DP, Besch HR Jr, Murphy WR, Hockel GM. Sympathetic nerve activity: role in regulation of blood pressure in the spontaenously hypertensive rat. Circ Res. 1976;38(6 Suppl 2):21–9.

    Article  CAS  PubMed  Google Scholar 

  3. • Li DP, Pan HL. Glutamatergic inputs in the hypothalamic paraventricular nucleus maintain sympathetic vasomotor tone in hypertension. Hypertension. 2007;49(4):916–25. https://doi.org/10.1161/01.HYP.0000259666.99449.74.

    Article  CAS  PubMed  Google Scholar 

  4. Esler M. Sympathetic nervous system: contribution to human hypertension and related cardiovascular diseases. J Cardiovasc Pharmacol. 1995;26(Suppl 2):S24–8.

    Article  CAS  PubMed  Google Scholar 

  5. Grassi G. Role of the sympathetic nervous system in human hypertension. J Hypertens. 1998;16(12 Pt 2):1979–87.

    Article  CAS  PubMed  Google Scholar 

  6. Greenwood JP, Stoker JB, Mary DA. Single-unit sympathetic discharge: quantitative assessment in human hypertensive disease. Circulation. 1999;100(12):1305–10.

    Article  CAS  PubMed  Google Scholar 

  7. Swanson LW, Sawchenko PE. Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci. 1983;6:269–324. https://doi.org/10.1146/annurev.ne.06.030183.001413.

    Article  CAS  PubMed  Google Scholar 

  8. Coote JH, Yang Z, Pyner S, Deering J. Control of sympathetic outflows by the hypothalamic paraventricular nucleus. Clin Exp Pharmacol Physiol. 1998;25(6):461–3.

    Article  CAS  PubMed  Google Scholar 

  9. Dampney RA, Horiuchi J, Killinger S, Sheriff MJ, Tan PS, McDowall LM. Long-term regulation of arterial blood pressure by hypothalamic nuclei: some critical questions. Clin Exp Pharmacol Physiol. 2005;32(5–6):419–25. https://doi.org/10.1111/j.1440-1681.2005.04205.x.

    Article  CAS  PubMed  Google Scholar 

  10. Pyner S, Coote JH. Identification of branching paraventricular neurons of the hypothalamus that project to the rostroventrolateral medulla and spinal cord. Neuroscience. 2000;100(3):549–56.

    Article  CAS  PubMed  Google Scholar 

  11. Ranson RN, Motawei K, Pyner S, Coote JH. The paraventricular nucleus of the hypothalamus sends efferents to the spinal cord of the rat that closely appose sympathetic preganglionic neurones projecting to the stellate ganglion. Exp Brain Res. 1998;120(2):164–72.

    Article  CAS  PubMed  Google Scholar 

  12. • Geraldes V, Goncalves-Rosa N, Liu B, Paton JF, Rocha I. Chronic depression of hypothalamic paraventricular neuronal activity produces sustained hypotension in hypertensive rats. Exp Physiol. 2014;99(1):89–100. https://doi.org/10.1113/expphysiol.2013.074823.

    Article  CAS  PubMed  Google Scholar 

  13. Eilam R, Malach R, Bergmann F, Segal M. Hypertension induced by hypothalamic transplantation from genetically hypertensive to normotensive rats. J Neurosci. 1991;11(2):401–11.

    CAS  PubMed  Google Scholar 

  14. Eilam R, Malach R, Segal M. Selective elimination of hypothalamic neurons by grafted hypertension-inducing neural tissue. J Neurosci. 1994;14(8):4891–902.

    CAS  PubMed  Google Scholar 

  15. Meldrum BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr. 2000;130(4S Suppl):1007S–15S.

    CAS  PubMed  Google Scholar 

  16. Palmada M, Centelles JJ. Excitatory amino acid neurotransmission. Pathways for metabolism, storage and reuptake of glutamate in brain. Front Biosci. 1998;3:d701–18.

    Article  CAS  PubMed  Google Scholar 

  17. Herman JP, Eyigor O, Ziegler DR, Jennes L. Expression of ionotropic glutamate receptor subunit mRNAs in the hypothalamic paraventricular nucleus of the rat. J Comp Neurol. 2000;422(3):352–62.

    Article  CAS  PubMed  Google Scholar 

  18. Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev. 1999;51(1):7–61.

    CAS  PubMed  Google Scholar 

  19. Mayer ML, Armstrong N. Structure and function of glutamate receptor ion channels. Annu Rev Physiol. 2004;66:161–81. https://doi.org/10.1146/annurev.physiol.66.050802.084104.

    Article  CAS  PubMed  Google Scholar 

  20. Conn PJ, Pin JP. Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol. 1997;37:205–37. https://doi.org/10.1146/annurev.pharmtox.37.1.205.

    Article  CAS  PubMed  Google Scholar 

  21. O'Connor JJ, Rowan MJ, Anwyl R. Long-lasting enhancement of NMDA receptor-mediated synaptic transmission by metabotropic glutamate receptor activation. Nature. 1994;367(6463):557–9. https://doi.org/10.1038/367557a0.

    Article  PubMed  Google Scholar 

  22. O'Connor JJ, Rowan MJ, Anwyl R. Tetanically induced LTP involves a similar increase in the AMPA and NMDA receptor components of the excitatory postsynaptic current: investigations of the involvement of mGlu receptors. J Neurosci. 1995;15(3 Pt 1):2013–20.

    PubMed  Google Scholar 

  23. Pin JP, Duvoisin R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology. 1995;34(1):1–26.

    Article  CAS  PubMed  Google Scholar 

  24. Mick G, Yoshimura R, Ohno K, Kiyama H, Tohyama M. The messenger RNAs encoding metabotropic glutamate receptor subtypes are expressed in different neuronal subpopulations of the rat suprachiasmatic nucleus. Neuroscience. 1995;66(1):161–73.

    Article  CAS  PubMed  Google Scholar 

  25. Gu G, Lorrain DS, Wei H, Cole RL, Zhang X, Daggett LP, et al. Distribution of metabotropic glutamate 2 and 3 receptors in the rat forebrain: implication in emotional responses and central disinhibition. Brain Res. 2008;1197:47–62. https://doi.org/10.1016/j.brainres.2007.12.057.

    Article  CAS  PubMed  Google Scholar 

  26. Ohishi H, Shigemoto R, Nakanishi S, Mizuno N. Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J Comp Neurol. 1993;335(2):252–66. https://doi.org/10.1002/cne.903350209.

    Article  CAS  PubMed  Google Scholar 

  27. •• Qiao X, Zhou JJ, Li DP, Pan HL. Src kinases regulate glutamatergic input to hypothalamic presympathetic neurons and sympathetic outflow in hypertension. Hypertension. 2017;69(1):154–62. https://doi.org/10.1161/HYPERTENSIONAHA.116.07947.

    Article  CAS  PubMed  Google Scholar 

  28. • Ye ZY, Li DP, Li L, Pan HL. Protein kinase CK2 increases glutamatergic input in the hypothalamus and sympathetic vasomotor tone in hypertension. J Neurosci. 2011;31(22):8271–9. https://doi.org/10.1523/JNEUROSCI.1147-11.2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gabor A, Leenen FH. Cardiovascular effects of angiotensin II and glutamate in the PVN of Dahl salt-sensitive rats. Brain Res. 2012;1447:28–37. https://doi.org/10.1016/j.brainres.2012.01.060.

    Article  CAS  PubMed  Google Scholar 

  30. Qi J, Zhang DM, Suo YP, Song XA, Yu XJ, Elks C, et al. Renin-angiotensin system modulates neurotransmitters in the paraventricular nucleus and contributes to angiotensin II-induced hypertensive response. Cardiovasc Toxicol. 2013;13(1):48–54. https://doi.org/10.1007/s12012-012-9184-9.

    Article  CAS  PubMed  Google Scholar 

  31. • Ye ZY, Li L, Li DP, Pan HL. Casein kinase 2-mediated synaptic GluN2A up-regulation increases N-methyl-D-aspartate receptor activity and excitability of hypothalamic neurons in hypertension. J Biol Chem. 2012;287(21):17438–46. https://doi.org/10.1074/jbc.M111.331165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li DP, Yang Q, Pan HM, Pan HL. Pre- and postsynaptic plasticity underlying augmented glutamatergic inputs to hypothalamic presympathetic neurons in spontaneously hypertensive rats. J Physiol. 2008;586(6):1637–47. https://doi.org/10.1113/jphysiol.2007.149732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. • Li DP, Zhou JJ, Pan HL. Endogenous casein kinase-1 modulates NMDA receptor activity of hypothalamic presympathetic neurons and sympathetic outflow in hypertension. J Physiol. 2015;593(19):4439–52. https://doi.org/10.1113/JP270831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. •• Li DP, Zhu LH, Pachuau J, Lee HA, Pan HL. mGluR5 upregulation increases excitability of hypothalamic presympathetic neurons through NMDA receptor trafficking in spontaneously hypertensive rats. J Neurosci. 2014;34(12):4309–17. https://doi.org/10.1523/JNEUROSCI.4295-13.2014.

    Article  PubMed  Google Scholar 

  35. • Glass MJ, Wang G, Coleman CG, Chan J, Ogorodnik E, Van Kempen TA, et al. NMDA receptor plasticity in the hypothalamic paraventricular nucleus contributes to the elevated blood pressure produced by angiotensin II. J Neurosci. 2015;35(26):9558–67. https://doi.org/10.1523/JNEUROSCI.2301-14.2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Marques-Lopes J, Lynch MK, Van Kempen TA, Waters EM, Wang G, Iadecola C, et al. Female protection from slow-pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors. Synapse. 2015;69(3):148–65. https://doi.org/10.1002/syn.21800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. • Marques-Lopes J, Van Kempen T, Waters EM, Pickel VM, Iadecola C, Milner TA. Slow-pressor angiotensin II hypertension and concomitant dendritic NMDA receptor trafficking in estrogen receptor beta-containing neurons of the mouse hypothalamic paraventricular nucleus are sex and age dependent. J Comp Neurol. 2014;522(13):3075–90. https://doi.org/10.1002/cne.23569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. •• Li DP, Byan HS, Pan HL. Switch to glutamate receptor 2-lacking AMPA receptors increases neuronal excitability in hypothalamus and sympathetic drive in hypertension. J Neurosci. 2012;32(1):372–80. https://doi.org/10.1523/JNEUROSCI.3222-11.2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hollmann M, Hartley M, Heinemann S. Ca2+ permeability of KA-AMPA--gated glutamate receptor channels depends on subunit composition. Science. 1991;252(5007):851–3.

    Article  CAS  PubMed  Google Scholar 

  40. Isaac JT, Ashby MC, McBain CJ. The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity. Neuron. 2007;54(6):859–71. https://doi.org/10.1016/j.neuron.2007.06.001.

    Article  CAS  PubMed  Google Scholar 

  41. Bowie D, Mayer ML. Inward rectification of both AMPA and kainate subtype glutamate receptors generated by polyamine-mediated ion channel block. Neuron. 1995;15(2):453–62.

    Article  CAS  PubMed  Google Scholar 

  42. Donevan SD, Rogawski MA. Intracellular polyamines mediate inward rectification of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Proc Natl Acad Sci U S A. 1995;92(20):9298–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Koh DS, Burnashev N, Jonas P. Block of native Ca(2+)-permeable AMPA receptors in rat brain by intracellular polyamines generates double rectification. J Physiol. 1995;486(Pt 2):305–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kimura R, Matsuki N. Protein kinase CK2 modulates synaptic plasticity by modification of synaptic NMDA receptors in the hippocampus. J Physiol. 2008;586(13):3195–206. https://doi.org/10.1113/jphysiol.2008.151894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Markram H, Segal M. Activation of protein kinase C suppresses responses to NMDA in rat CA1 hippocampal neurones. J Physiol. 1992;457:491–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yu XM, Askalan R, Keil GJ 2nd, Salter MW. NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science. 1997;275(5300):674–8.

    Article  CAS  PubMed  Google Scholar 

  47. Sanz-Clemente A, Gray JA, Ogilvie KA, Nicoll RA, Roche KW. Activated CaMKII couples GluN2B and casein kinase 2 to control synaptic NMDA receptors. Cell Rep. 2013;3(3):607–14. https://doi.org/10.1016/j.celrep.2013.02.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Taniguchi S, Nakazawa T, Tanimura A, Kiyama Y, Tezuka T, Watabe AM, et al. Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour. EMBO J. 2009;28(23):3717–29. https://doi.org/10.1038/emboj.2009.300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Donella-Deana A, Cesaro L, Sarno S, Ruzzene M, Brunati AM, Marin O, et al. Tyrosine phosphorylation of protein kinase CK2 by Src-related tyrosine kinases correlates with increased catalytic activity. Biochem J. 2003;372(Pt 3):841–9. https://doi.org/10.1042/BJ20021905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Venerando A, Ruzzene M, Pinna LA. Casein kinase: the triple meaning of a misnomer. Biochem J. 2014;460(2):141–56. https://doi.org/10.1042/BJ20140178.

    Article  CAS  PubMed  Google Scholar 

  51. Agostinis P, Marin O, James P, Hendrix P, Merlevede W, Vandenheede JR, et al. Phosphorylation of the phosphatase modulator subunit (inhibitor-2) by casein kinase-1. Identification of the phosphorylation sites. FEBS Lett. 1992;305(2):121–4.

    Article  CAS  PubMed  Google Scholar 

  52. Wang LY, Orser BA, Brautigan DL, MacDonald JF. Regulation of NMDA receptors in cultured hippocampal neurons by protein phosphatases 1 and 2A. Nature. 1994;369(6477):230–2. https://doi.org/10.1038/369230a0.

    Article  CAS  PubMed  Google Scholar 

  53. Westphal RS, Tavalin SJ, Lin JW, Alto NM, Fraser ID, Langeberg LK, et al. Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. Science. 1999;285(5424):93–6.

    Article  CAS  PubMed  Google Scholar 

  54. Lieberman DN, Mody I. Casein kinase-II regulates NMDA channel function in hippocampal neurons. Nat Neurosci. 1999;2(2):125–32. https://doi.org/10.1038/5680.

    Article  CAS  PubMed  Google Scholar 

  55. Tong G, Shepherd D, Jahr CE. Synaptic desensitization of NMDA receptors by calcineurin. Science. 1995;267(5203):1510–2.

    Article  CAS  PubMed  Google Scholar 

  56. • Li DP, Pan HL. Increased group I metabotropic glutamate receptor activity in paraventricular nucleus supports elevated sympathetic vasomotor tone in hypertension. Am J Physiol Regul Integr Comp Physiol. 2010;299(2):R552–61. https://doi.org/10.1152/ajpregu.00195.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. • Ye ZY, Li DP, Pan HL. Regulation of hypothalamic presympathetic neurons and sympathetic outflow by group II metabotropic glutamate receptors in spontaneously hypertensive rats. Hypertension. 2013;62(2):255–62. https://doi.org/10.1161/HYPERTENSIONAHA.113.01466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding Information

Work conducted in the authors’ laboratory was supported by grants HL131161 and MH096086 from the National Institutes of Health.

Author information

Authors and Affiliations

  1. Center for Neuroscience and Pain Research, Division of Anesthesiology and Critical Care, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    De-Pei Li & Hui-Lin Pan

Authors
  1. De-Pei Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Hui-Lin Pan
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

All authors contributed to the manuscript writing. The authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Hui-Lin Pan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Hypertension and the Brain

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, DP., Pan, HL. Glutamatergic Regulation of Hypothalamic Presympathetic Neurons in Hypertension. Curr Hypertens Rep 19, 78 (2017). https://doi.org/10.1007/s11906-017-0776-4

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11906-017-0776-4

Keywords