The inhibitory action of an excitatory neurotransmitter

Abstract

Glutamate binds to a wide array of ionotropic and metabotropic receptors in the brain. Although the action of glutamate is dependent on the type of receptor activated, its action is mainly excitatory. One subtype of ionotropic receptors, the NMDA receptor, contributes to fast synaptic transmission and plays an important role in phenomena such as long-term potentiation and cytotoxicity. Ca2+-activated K+ channels (BKCa channels) are responsible for regulating neuronal excitability by hyperpolarizing the membrane following propagation of an action potential. NMDA receptors are highly permeable to Ca2+ and it has been suggested that increases in the intracellular concentration of Ca2+ following NMDA receptor activation could lead to the activation of BKCa channels, although a functional coupling between the two systems has not been demonstrated.Now, Isaacson and Murphy [1xGlutamate-mediated extrasynaptic inhibition: direct coupling of NMDA receptors to Ca2+-activated K+ channels. Isaacson, J.S. and Murphy, G.J. Neuron. 2001; 31: 1027–1034Abstract | Full Text | Full Text PDF | PubMed | Scopus (105)See all References][1] report a different role for NMDA receptors at synapses between mitral and granule cells in olfactory bulb slices. Glutamate, applied exogenously to the soma of granule neurons, evokes a hyperpolarizing current that is blocked by NMDA receptor antagonists. This response does not require voltage-gated Ca2+ channels or release of Ca2+ from intracellular stores, but depends on the activation of BKCa channels. A slow inhibitory postsynaptic current (IPSC) mediated by NMDA receptors and BKCa channels was also recorded in granule neurons in response to repetitive activation of glutamatergic nerve endings. The IPSC was enhanced markedly by increasing the intensity of the stimulation and following inhibition of the glutamate transporter, suggesting that glutamate is spilling over from the synaptic cleft and thereby exciting extrasynaptic NMDA receptors located in close vicinity to BKCa channels.Changes in transmitter release owing to different stimulation intensity could control the relative degree of excitation or inhibition mediated by NMDA receptors in this way, regulating the dynamic circuitry of the bulb. Isaacson and Murphy provide direct evidence for a novel inhibitory action of glutamate derived from a direct coupling of NMDA receptor to BKCa channels. Determination of whether this process is also relevant at other synapses in the CNS will help to understand the response of drugs that modulate NMDA receptor function.