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1 Department of Anatomy, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
2 Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK
NMDA receptors regulate burst firing of dopaminergic neurones in the substantia nigra pars compacta (SNc) and may contribute to excitotoxic cell death in Parkinson's disease (PD). In order to investigate the subunit composition of functional NMDA receptors in identified rat SNc dopaminergic neurones, we have analysed the properties of individual NMDA receptor channels in outside-out patches. NMDA (100 nM) activated channels corresponding to four chord conductances of 18, 30, 41 and 54 pS. Direct transitions were observed between all conductance levels. Between 18 pS and 41 pS conductance levels, direct transitions were asymmetric, consistent with the presence of NR2D-containing NMDA receptors. Channel activity in response to 100 nM or 200 µM NMDA was not affected by zinc or TPEN (N,N,N',N'-tetrakis-[2-pyridylmethyl]-ethylenediamine), indicating that SNc dopaminergic neurones do not contain functional NR2A subunits. The effect of the NR2B antagonist ifenprodil was complex: 1 µM ifenprodil reduced open probability, while 10 µM reduced channel open time but had no effect on open probability of channels activated by 100 nM NMDA. When the concentration of NMDA was increased to 200 µM, ifenprodil (10 µM) produced the expected reduction in open probability. These results indicate that NR2B subunits are present in SNc dopaminergic neurones. Taken together, these findings indicate that NR2D and NR2B subunits form functional NMDA receptor channels in SNc dopaminergic neurones, and suggest that they may form a triheteromeric NMDA receptor composed of NR1/NR2B/NR2D subunits.
(Received 28 July 2005;
accepted after revision 30 August 2005;
first published online 1 September 2005)
Corresponding author A. J. Gibb: Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Email: a.gibb{at}ucl.ac.uk
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