TRPM7 in cerebral ischemia and potential target for drug development in stroke

Abstract

Searching for effective pharmacological agents for stroke treatment has largely been unsuccessful. Despite initial excitement, antagonists for glutamate receptors, the most studied receptor channels in ischemic stroke, have shown insufficient neuroprotective effects in clinical trials. Outside the traditional glutamate-mediated excitotoxicity, recent evidence suggests few non-glutamate mechanisms, which may also cause ionic imbalance and cell death in cerebral ischemia. Transient receptor potential melastatin 7 (TRPM7) is a Ca(2+) permeable, non-selective cation channel that has recently gained attention as a potential cation influx pathway involved in ischemic events. Compelling new evidence from an in vivo study demonstrated that suppression of TRPM7 channels in adult rat brain in vivo using virally mediated gene silencing approach reduced delayed neuronal cell death and preserved neuronal functions in global cerebral ischemia. In this review, we will discuss the current understanding of the role of TRPM7 channels in physiology and pathophysiology as well as its therapeutic potential in stroke.

Figure 1

Schematic diagram showing proposed transmembrane topology of TRPM7. (A) The putative membrane topology of a single subunit of TRPM7 is shown. Each subunit has six transmembrane (TM) spanning domains (S1–S6) with a re-entrant pore-forming loop between the fifth (S5) and sixth (S6) segments. The intracellularly located N-terminus has another hydrophobic region (H1) and four regions of TRPM subfamily homology domain (MHD). The intracellularly located C-terminus contains a TRP box of ∼25 highly conserved residues (TRP) and a coiled-coil domain (CCD). The distal C-terminus has an atypical serine/threonine protein kinase domain. As indicated in the figure, TRPM7 is a non-selective cation channel that conducts both monovalent ions (eg, Na⁺ and K⁺) and divalent ions (eg, Ca²⁺, Mg²⁺ and other trace metal ions). (B) Representative current-voltage (I-V) relationship of TRPM7.

Figure 2

Working model of TRPM7 activation during cerebral ischemia. (A) During the early phase of an ischemic attack, an increase in the extracellular glutamate activates NMDA receptors. Ca²⁺ influx due to activated NMDA receptors stimulates: (i) production of nitric oxide (NO) by nitric oxide synthase (NOS) and (ii) production of superoxide (O₂⁻) from mitochondria. NO and O₂⁻ combine to produce highly reactive species peroxynitrite (ONOO⁻). Along with factors, such as decrease in pH, that are associated with ischemia, these free radicals promote sustained activation of TRPM7, which leads to further Ca²⁺ build-up in the intracellular space. (B) Consequences of unchecked Ca²⁺ influx. Increased intracellular Ca²⁺ concentration may lead to excitotoxicity, oxidative stress, inflammatory processes and eventual cell death.