N-methyl-D-aspartate receptor activation increases cAMP levels and voltage-gated Ca2+ channel activity in area CA1 of hippocampus.
Tetanic stimulation of the Schaffer collateral inputs into area CA1 of the hippocampus causes N-methyl-D-aspartate (NMDA) receptor activation, an effect that contributes to the induction of long-term potentiation (LTP) in this region. The present studies demonstrate that LTP-inducing tetanic stimulation in rat hippocampal area CA1 elicited increased levels of cAMP. The elevation of cAMP was blocked by the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV). Bath application of NMDA also resulted in an increase in cAMP in CA1, an effect that was blocked by both APV and removal of extracellular Ca2+. These findings suggest that activation of NMDA receptors elicits a Ca(2+)-dependent increase in cAMP, and taken together with the data from tetanic stimulation, suggest that NMDA-receptor-mediated increases in cAMP could play a role in the induction of LTP in area CA1. One role for cAMP may be to increase Ca2+ influx through voltage-gated Ca2+ channels, as it was observed that application of either 8-bromo-cAMP or NMDA increased the fractional open time of high-threshold Ca2+ channels in CA1 pyramidal cells. Our results raise the possibility that a positive-feedback loop for Ca2+ influx in area CA1 exists. In this model, NMDA receptor-mediated Ca2+ influx leads to an enhancement of further Ca2+ influx via intermediate steps of increased cAMP and subsequent increased voltage-gated Ca2+ channel activity.
Division of Neuroscience, Baylor College of Medicine, Houston, TX 77030.
D M
DM
Chetkovich
R
R
Gray
D
D
Johnston
J D
JD
Sweatt
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology*; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D004533:Egtazic Acid / Q000494:pharmacology; D004558:Electric Stimulation; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*
D015220:Calcium Channels; D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D015124:8-Bromo Cyclic Adenosine Monophosphate; D018698:Glutamic Acid; D004533:Egtazic Acid; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D000242:Cyclic AMP; D002118:Calcium