They are differentiated from one another by cation permeability as well as differential sensitivity to pharmacological agonists/antagonists. All ionotropic glutamate receptors are permeable to Na+ and K+, and it is the influx of Na+ and outflow of K+ through these channels that contribute to membrane depolarization and generation of the action potential. The NMDA receptor also has a Ca++ channel that is blocked by Mg++ ions in the resting state, but under conditions of local membrane depolarization, Mg++ is displaced and the channel becomes permeable to Ca++; influx of Ca++ tends to further depolarize the cell, and is thought also to contribute to Ca++ mediated neuronal injury under conditions of excessive neuronal activation (such as status epilepticus and ischemia), potentially leading to cell death, a process termed excitotoxicity. The other major type of glutamate receptor is the metabotropic receptor, which functions by means of receptor-activated signal transduction involving membrane-associated G-proteins (Appendix A, Table 2). There are at least 3 subtypes of metabotropic receptors, based on differential agonist potency, mechanism of signal transduction, and pre- versus post-synaptic localization.