Рафаэль Юсте, Стивен А. Сигельбаум (Rafael Yuste, Steven A. Siegelbaum)NMDA Receptors Have Unique Biophysical and Pharmacological Properties
The NMDA receptor has several interesting properties that distinguish it from AMPA receptors. As mentioned earlier, NMDA receptors have a distinctively high permeability to Ca2+. In addition, the NMDA receptor is unique among ligand-gated channels thus far characterized because its opening depends on membrane voltage as well as transmitter binding.
The voltage dependence is caused by a mechanism that is quite different from that employed by the voltage-gated channels that generate the action potential. In the latter, changes in membrane potential are translated into conformational changes in the channel by an intrinsic voltage sensor. In the NMDA receptors, however, depolarization removes an extrinsic plug from the channel. At the resting membrane potential (−65 mV), extracellular Mg2+ binds tightly to a site in the pore of the channel, blocking ionic current. But when the membrane is depolarized (for example, by the opening of AMPA receptor-channels), Mg2+ is expelled from the channel by electrostatic repulsion, allowing Na+, K+, and Ca2+ to flow (Figure 13–8). The NMDA receptor has the further interesting property of being inhibited by the hallucinogenic drug phencyclidine (PCP, also known as angel dust) and the experimental compound MK801. Both drugs bind to a site in the pore of the channel that is distinct from the Mg2+ binding site (Figure 13–3A).
Figure 13–8 Opening of individual NMDA receptor-channels depends on membrane potential in addition to glutamate.
These patch-clamp recordings are from individual NMDA receptor- channels (from rat hippocampal cells in culture). Downward deflections indicate pulses of inward (negative) current; upward deflections indicate outward (positive) current. (Reproduced, with permission, from J. Jen and C.F. Stevens.)
A. When Mg2+ is present in normal concentration in the extracellular solution (1.2 mM), the channel is largely blocked at the resting potential (−60 mV). At negative membrane potentials, only brief, flickering, inward currents are seen upon channel opening because of the Mg2+ block. Substantial depolarization to voltages positive to the reversal potential of 0 mV (to +30 mV or +60 mV) relieves the Mg2+ block, permitting longerlasting pulses of outward current through the channel.