Nickel Blocks the Potentiation of NMDA Receptors at Alkaline pH
Abstract number :
1.018
Submission category :
Year :
2001
Submission ID :
3070
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
E.J. Katz, PhD, Neurology, Univ. of Maryland Sch. of Med., Baltimore, MD; C-M. Tang, MD PhD, Neurology, Univ. of Maryland Sch. of Med., Baltimore, MD
RATIONALE: NMDA receptors are major contributors to neuronal excitability. A number of endogenous allosteric modulators regulate NMDA function and protect against receptor overactivation, among these is proton modulation. NMDA receptors are inhibited at acidic pH and enhanced at alkaline pH. Respiratory alkalosis may act through proton modulation to lower the seizure threshold during hyperventilation. A better understanding of proton modulation may facilitate the development of better pharmacologic agents to control neuronal excitability.
METHODS: Whole-cell patch clamp recordings were obtained from cultured hippocampal neurons while subjected to rapid perfusion with solutions buffered to pH 6.8 and 8.0 containing NMDA and varied concentrations of transition metal cations (i.e. nickel, cobalt, cadmium, and zinc).
RESULTS: In contrast to previous reports at pH 7.3 we found that nickel primarily blocked NMDA response in a voltage independent manner. More interestingly, the antagonistic action of nickel was highly pH dependent. Whereas 100 uM nickel did not block the NMDA response at pH 6.8, the same concentration of nickel strongly blocked the NMDA response at pH 8.0. We then examined the effect of nickel on proton modulation. In sharp contrast to the actions of zinc, nickel attenuated the potentiation of the NMDA response at alkaline pH.
CONCLUSIONS: Nickel has an effect on NMDA receptors that is unique from zinc and its binding site is unlikely to be the same as that for zinc. We postulate that nickel more directly targets the proton modulation sites of NMDA receptors.
Support: NIH and VA Medical Research