Protein kinase C reduces Mg²⁺ block of NMDA-receptor channels as a mechanism of modulation

Abstract

THE roles of N-methyl-D-aspartate (NMDA) receptors and protein kinase C (PKC) are critical in generating and maintaining a variety of sustained neuronal responses. In the nociceptive (pain-sensing) system, tissue injury or repetitive stimulation of small-diameter afferent fibres triggers a dramatic increase in discharge (wind-up) or prolonged depolarization of spinal cord neurons. This central sensitization can neither be induced nor maintained when NMDA receptor channels are blocked^1,2. In the trigeminal subnu-cleus caudalis (a centre for processing nociceptive information from the orofacial areas³), a µ-opioid receptor agonist causes a sustained increase in NMDA-activated currents by activating intracellular PKC⁴. There is also evidence that PKC enhances NMDA-receptor-mediated glutamate responses^4–7 and regulates long-term potentiation of synaptic transmission^8–14. Despite the importance of NMDA-receptors and PKC, the mechanism by which PKC alters the NMDA response has remained unclear. Here we examine the actions of intracellularly applied PKC on NMDA-activated currents in isolated trigeminal neurons. We find that PKC potentiates the NMDA response by increasing the probability of channel openings and by reducing the voltage-dependent Mg²⁺ block of NMDA-receptor channels.