title: mGluR5 Upregulation increases excitability of hypothalamic presympathetic neurons through NMDA receptor trafficking in spontaneously hypertensive rats.
abstract: The hypothalamic paraventricular nucleus (PVN) is critically involved in elevated sympathetic output and the development of hypertension. However, changes in group I metabotropic glutamate receptors (mGluR1 and mGluR5) and their relevance to the hyperactivity of PVN presympathetic neurons in hypertension remain unclear. Here, we found that selectively blocking mGluR5 significantly reduced the basal firing activity of spinally projecting PVN neurons in spontaneously hypertensive rats (SHRs), but not in normotensive Wistar-Kyoto (WKY) rats. However, blocking mGluR1 had no effect on the firing activity of PVN neurons in either group. The mRNA and protein levels of mGluR5 in the PVN and rostral ventrolateral medulla were significantly higher in SHRs than in WKY rats. The group I mGluR selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) similarly increased the firing activity of PVN neurons in WKY rats and SHRs. In addition, blocking NMDA receptors (NMDARs) through bath application or intracellular dialysis not only decreased the basal firing in SHRs, but also eliminated DHPG-induced excitation of spinally projecting PVN neurons. DHPG significantly increased the amplitude of NMDAR currents without changing their decay kinetics. Interestingly, DHPG still increased the amplitude of NMDAR currents and caused reappearance of functional NMDAR channels after initially blocking NMDARs. In addition, protein kinase C (PKC) inhibition or intracellular dialysis with synaptosomal-associated protein of 25 kDa (SNAP-25)-blocking peptide abolished DHPG-induced increases in NMDAR currents of PVN neurons in SHRs. Our findings suggest that mGluR5 in the PVN is upregulated in hypertension and contributes to the hyperactivity of PVN presympathetic neurons through PKC- and SNAP-25-mediated surface expression of NMDARs.
authors.affiliation: Center for Neuroscience and Pain Research, Division of Anesthesiology and Critical Care, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, and Programs in Neuroscience and Experimental Therapeutics, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77225.
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Li
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Zhu
authors.forename: Judith
authors.initials: J
authors.lastname: Pachuau
authors.forename: Hae-Ahm
authors.initials: HA
authors.lastname: Lee
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D016194:Receptors, N-Methyl-D-Aspartate; C079694:alpha-methyl-4-carboxyphenylglycine; C121465:6-methyl-2-(phenylethynyl)pyridine; D005998:Glycine