Mixed‐agonist action of excitatory amino acids on mouse spinal cord neurones under voltage clamp.

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Abstract
Neurons from the ventral half of mouse embryo spinal cord were grown in tissue culture and voltage clamped with 2 micro-electrodes. The current-voltage relation of responses evoked by brief pressure applications of excitatory amino acids was examined over a membrane potential range of -100 to +70 mV. Three types of current-voltage relations were observed. Responses to kainic and quisqualic acids were relatively linear within .+-. 20 mV of the resting potential. N-methyl-D-aspartate (NMDA) and L-aspartic acid responses had a negative slope conductance at membrane potentials more negative than -30 mV. Over the same potential range the slope conductance of responses evoked by L-glutamic and L-homocysteic acids was close to zero. The membrane potential-chord conductance relation of the ionic mechanism activated by excitatory amino acids, derived using the driving force for ionic current, showed 2 types of behavior. The conductance linked to NMDA receptors was highly voltage sensitive and increased on depolarization. A much weaker voltage sensitivity was observed for responses evoked by kainic and quisqualic acids. L-glutamic and L-homocysteic acid responses behaved as though due to simultaneous activation of both NMDA and either kainate or quisqualate receptors. In the presence of the NMDA receptor antagonist (.+-.)-2-aminophosphonovaleric acid (2-APV) the response to L-glutamate became less voltage sensitive and resembled responses evoked by kainate or quisqualate. Simultaneous activation of both conductance mechanisms by mixtures of kainate and NMDA produced current-voltage and membrane potential-chord conductance relations similar to those of L-glutamate. The voltage sensitivity of the L-glutamate response was inversely related to the dose. For low doses of L-glutamate the slope conductance of responses recorded near the resting potential was close to zero. Larger doses of L-glutamate evoked responses with a voltage sensitivity similar to that of kainate. L-Glutamate probably acts as a mixed agonist at both NMDA and non-NMDA receptors. This can explain the results of previous experiments that failed to demonstrate a membrane resistance change during L-glutamate-induced depolarizations.