Ionotropic receptors and ion channels in ischemic neuronal death and dysfunction

Abstract

Loss of energy supply to neurons during stroke induces a rapid loss of membrane potential that is called the anoxic depolarization. Anoxic depolarizations result in tremendous physiological stress on the neurons because of the dysregulation of ionic fluxes and the loss of ATP to drive ion pumps that maintain electrochemical gradients. In this review, we present an overview of some of the ionotropic receptors and ion channels that are thought to contribute to the anoxic depolarization of neurons and subsequently, to cell death. The ionotropic receptors for glutamate and ATP that function as ligand-gated cation channels are critical in the death and dysfunction of neurons. Interestingly, two of these receptors (P2X7 and NMDAR) have been shown to couple to the pannexin-1 (Panx1) ion channel. We also discuss the important roles of transient receptor potential (TRP) channels and acid-sensing ion channels (ASICs) in responses to ischemia. The central challenge that emerges from our current understanding of the anoxic depolarization is the need to elucidate the mechanistic and temporal interrelations of these ion channels to fully appreciate their impact on neurons during stroke.

Figure 1

Key ion channels that contribute to cell death signaling cascades during ischemia. For clarity, channels in the post-synpatic membrane are highlighted, but it is important to note that both pre-synpatic and astrocytic channels are also likely critical. Ischemia triggers enhanced presynaptic glutamate release and reversal of the astrocytic glutamate reuptake transporter (EAAT1), amounting to a dramatic increase in glutamatergic signaling via postsynaptic NMDARs and AMPARs. Ca²⁺ through NMDARs and GluA2-lacking AMPARs can stimulate NO production by Ca²⁺-dependent nNOS, which can react with reactive oxygen species (ROS) to form highly damaging intermediates. NO and NO-ROS reaction products (i.e. peroxynitrite) may activate TRPM2/7 and Panx1 channels. Retrograde diffusion of NO can enhance presynaptic glutamate release, further exacerbating postsynaptic excitotoxicity. Decreases in extracellular pH leads to ASIC opening and Ca²⁺-influx (for ASIC-1a homomers), which may in turn contribute to cell death. Increases in extracellular ATP concentrations stimulate P2X7 opening, possibly activating Panx1 channels via Src Family Kinases (SFK), as well as stimulating ERK1/2 function to induce cell death. Activation of any/all of the ion channels mentioned here will yield an increase in intracellular Ca²⁺ levels, which can activate downstream caspases, calpains, and trigger mitochondrial permeability transition; all of which have been implicated in neuronal dysfunction/apoptosis/necrosis.