TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis

Abstract

In multiple sclerosis, an inflammatory disease of the central nervous system (CNS), axonal and neuronal loss are major causes for irreversible neurological disability. However, which molecules contribute to axonal and neuronal injury under inflammatory conditions remains largely unknown. Here we show that the transient receptor potential melastatin 4 (TRPM4) cation channel is crucial in this process. TRPM4 is expressed in mouse and human neuronal somata, but it is also expressed in axons in inflammatory CNS lesions in experimental autoimmune encephalomyelitis (EAE) in mice and in human multiple sclerosis tissue. Deficiency or pharmacological inhibition of TRPM4 using the antidiabetic drug glibenclamide resulted in reduced axonal and neuronal degeneration and attenuated clinical disease scores in EAE, but this occurred without altering EAE-relevant immune function. Furthermore, Trpm4(-/-) mouse neurons were protected against inflammatory effector mechanisms such as excitotoxic stress and energy deficiency in vitro. Electrophysiological recordings revealed TRPM4-dependent neuronal ion influx and oncotic cell swelling upon excitotoxic stimulation. Therefore, interference with TRPM4 could translate into a new neuroprotective treatment strategy.

Negatively Charged Amino Acids Near and in Transient Receptor Potential (TRP) Domain of TRPM4 Channel Are One Determinant of Its Ca2+ Sensitivity

“…As manganese poisoning progresses, catecholamine levels decrease, most likely due to the loss of nigrostriatal dopaminergic neurons, and consequently, parkinsonian-like symptoms ensue (37). Intriguingly, the pathological activation of TRPM4 in neurons has been shown to mediate axonal and neuronal degeneration (13). Therefore, the contribution of TRPM4 activation by Mn 2ϩ to the pathogenesis of manganism needs to be addressed.…”

“…Additionally, its mutations in the TRPM4 gene have been associated with cardiac conduction dysfunction in human patients (4, 10 -12). Furthermore, it has been shown that TRPM4 mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis (13).…”

Effects of Selected OATP and/or ABC Transporter Inhibitors on the Brain and Whole-Body Distribution of Glyburide

“…It inhibits sulfonylurea receptor 1 (SUR1, ABCC8), the regulatory subunit of the pancreatic potassium efflux channel (K ATP ) of the ATP-binding cassette (ABC) family. Recent reports have revealed that GLB may also have beneficial effects in acute ischemic, traumatic, and inflammatory central nervous system (CNS) injuries and diseases via its affinity for transient receptor potential melastatin 4 in the brain (1,2).…”

Plasticity of Th17 Cells in Autoimmune Kidney Diseases

“…Experimental autoimmune encephalomyelitis (EAE) was induced by immunization of female mice (12-14 wk) s.c. with 200 mg myelin oligodendrocyte glycoprotein peptide fragment 35-55 (NeoMPS, San Diego, CA) in CFA (BD Biosciences, Franklin Lakes, NJ) containing 4 mg/ml Mycobacterium tuberculosis (H37Ra; BD Biosciences), as described previously (26). We injected 200 ng pertussis toxin (Merck Millipore, Darmstadt, Germany) i.v.…”

“…on the day of immunization and 48 h later. Mice were scored for clinical signs by the following system: 0, no clinical deficits; 1, tail weakness; 2, hind limb paresis; 3, partial hind limb paralysis; 3.5, full hind limb paralysis; 4, full hind limb paralysis and forelimb paresis; and 5, premorbid or dead (26). Mice were analyzed at day 14 after EAE induction.…”