PMID- 28378360
OWN - NLM
STAT- MEDLINE
DCOM- 20180417
LR  - 20240326
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Print)
IS  - 0022-3751 (Linking)
VI  - 595
IP  - 14
DP  - 2017 Jul 15
TI  - An increased extrasynaptic NMDA tone inhibits A-type K(+) current and increases 
      excitability of hypothalamic neurosecretory neurons in hypertensive rats.
PG  - 4647-4661
LID - 10.1113/JP274327 [doi]
AB  - KEY POINTS: A functional coupling between extrasynaptic NMDA receptors (eNMDARs) 
      and the A-type K(+) current (I(A) ) influences homeostatic firing responses of 
      magnocellular neurosecretory cells (MNCs) to a physiological challenge. However, 
      whether an altered eNMDAR-I(A) coupling also contributes to exacerbated MNC 
      activity and neurohumoral activation during disease states is unknown. We show 
      that activation of eNMDARs by exogenously applied NMDA inhibited I(A) in MNCs 
      obtained from sham, but not in MNCs from renovascular hypertensive (RVH) rats. 
      Neither the magnitude of the exogenously evoked NMDA current nor the expression 
      of NMDAR subunits were altered in RVH rats. Conversely, we found that a larger 
      endogenous glutamate tone, which was not due to blunted glutamate transport 
      activity, led to the sustained activation of eNMDARs that tonically inhibited 
      I(A) , contributing in turn to higher firing activity in RVH rats. Our studies 
      show that exacerbated activation of eNMDARs by endogenous glutamate contributes 
      to tonic inhibition of I(A) and enhanced MNC excitability in RVH rats. ABSTRACT: 
      We recently showed that a functional coupling between extrasynaptic NMDA 
      receptors (eNMDARs) and the A-type K(+) current (I(A) ) influences the firing 
      activity of hypothalamic magnocellular neurosecretory neurons (MNCs), as well as 
      homeostatic adaptive responses to a physiological challenge. Here, we aimed to 
      determine whether changes in the eNMDAR-I(A) coupling also contributed to 
      exacerbated MNC activity during disease states. We used a combination of 
      patch-clamp electrophysiology and real-time PCR in MNCs in sham and renovascular 
      hypertensive (RVH) rats. Activation of eNMDARs by exogenously applied NMDA 
      inhibited I(A) in sham rats, but this effect was largely blunted in RVH rats. The 
      blunted response was not due to changes in eNMDAR expression and/or function, 
      since neither NMDA current magnitude or reversal potential, nor the levels of 
      NR1-NR2A-D subunit expression were altered in RVH rats. Conversely, we found a 
      larger endogenous glutamate tone, resulting in the sustained activation of 
      eNMDARs that tonically inhibited I(A) and contributed also to higher ongoing 
      firing activity in RVH rats. The enhanced endogenous glutamate tone in RVH rats 
      was not due to blunted glutamate transporter activity. Rather, a higher 
      transporter activity was observed, which possibly acted as a compensatory 
      mechanism in the face of the elevated endogenous tone. In summary, our studies 
      indicate that an elevated endogenous glutamate tone results in an exacerbated 
      activation of eNMDARs, which in turn contributes to diminished I(A) magnitude and 
      increased firing activity of MNCs from hypertensive rats.
CI  - (c) 2017 The Authors. The Journal of Physiology (c) 2017 The Physiological Society.
FAU - Zhang, Meng
AU  - Zhang M
AD  - Department of Physiology, Medical College of Georgia, Augusta University, 1120 
      15th Street, Augusta, GA, 30912, USA.
FAU - Biancardi, Vinicia C
AU  - Biancardi VC
AD  - Department of Physiology, Medical College of Georgia, Augusta University, 1120 
      15th Street, Augusta, GA, 30912, USA.
FAU - Stern, Javier E
AU  - Stern JE
AUID- ORCID: 0000-0002-9310-0486
AD  - Department of Physiology, Medical College of Georgia, Augusta University, 1120 
      15th Street, Augusta, GA, 30912, USA.
LA  - eng
GR  - R01 HL112225/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20170523
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 6384-92-5 (N-Methylaspartate)
SB  - IM
CIN - J Physiol. 2017 Jul 15;595(14):4583-4584. PMID: 28548235
MH  - Animals
MH  - Hypertension, Renal/*physiopathology
MH  - Male
MH  - N-Methylaspartate/pharmacology
MH  - Neurons/*physiology
MH  - Rats, Wistar
MH  - Receptors, N-Methyl-D-Aspartate/*physiology
MH  - Supraoptic Nucleus/*physiology
PMC - PMC5509869
OTO - NOTNLM
OT  - NMDA
OT  - glutamate
OT  - hypothalamus
OT  - potassium current
EDAT- 2017/04/06 06:00
MHDA- 2018/04/18 06:00
PMCR- 2018/07/15
CRDT- 2017/04/06 06:00
PHST- 2017/03/16 00:00 [received]
PHST- 2017/03/31 00:00 [accepted]
PHST- 2017/04/06 06:00 [pubmed]
PHST- 2018/04/18 06:00 [medline]
PHST- 2017/04/06 06:00 [entrez]
PHST- 2018/07/15 00:00 [pmc-release]
AID - TJP12378 [pii]
AID - 10.1113/JP274327 [doi]
PST - ppublish
SO  - J Physiol. 2017 Jul 15;595(14):4647-4661. doi: 10.1113/JP274327. Epub 2017 May 
      23.