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Volume 17, Number 22, Issue of November 15, 1997 pp. 8676-8686

Ca²⁺ Influx Amplifies Protein Kinase C Potentiation of Recombinant NMDA Receptors

Received June 4, 1997; revised Aug. 18, 1997; accepted Aug 26, 1997.

Xin Zheng, Ling Zhang, Alice P. Wang, Michael V. L. Bennett, and R. Suzanne Zukin

Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Protein kinase C (PKC) potentiates NMDA receptors in hippocampal, trigeminal, and spinal neurons. Although PKC phosphorylates the NMDA receptor subunit NR1 at four residues within the C terminal splice cassette C1, the molecular mechanisms underlying PKC potentiation of NMDA responses are not yet known. The present study examined the role of Ca²⁺ in PKC potentiation of recombinant NMDA receptors expressed in Xenopus oocytes. We found that Ca²⁺ influx through PKC-potentiated NMDA receptors can further increase the NMDA response ("Ca²⁺ amplification"). Ca²⁺ amplification required a rise in intracellular Ca²⁺ concentration at or near the intracellular end of the channel and was independent of Ca²⁺-activated Cl current. Ca²⁺ amplification depended on extracellular Ca²⁺ concentration during NMDA application and not during PKC activation. Ca²⁺ amplification was reduced by the membrane-permeant Ca²⁺-chelating agent BAPTA-AM. Mutant receptors with greatly reduced Ca²⁺ permeability did not exhibit Ca²⁺ amplification. Receptors containing the NR1 N-terminal splice cassette showed more Ca²⁺ amplification, possibly because of their larger basal current and therefore greater Ca²⁺ influx. Contrary to expectation, splicing out the two C-terminal splice cassettes of NR1 enhanced PKC potentiation in a manner independent of extracellular Ca²⁺. This observation indicates that PKC potentiation does not require phosphorylation of the C1 cassette of the NR1 subunit. PKC potentiation of NMDA receptors in vivo is likely to be affected by Ca²⁺ amplification of the potentiated signal; the degree of amplification will depend in part on alternative splicing of the NR1 subunit, which is regulated developmentally and in a cell-specific manner.

Key words: protein kinase C; NMDA receptors; alternative RNA splicing; TPA; BAPTA; Xenopus oocyte

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