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.

The Transient receptor potential (TRP) family of cation channels is a large protein family, which is mainly structurally uniform. Proteins consist typically of six transmembrane domains and mostly four subunits are necessary to form a functional channel. Apart from this, TRP channels display a wide variety of activation mechanisms (ligand binding, G-protein coupled receptor dependent, physical stimuli such as temperature, pressure, etc.) and ion selectivity profiles (from highly Ca(2+) selective to non-selective for cations). They have been described now in almost every tissue of the body, including peripheral and central neurons. Especially in the sensory nervous system the role of several TRP channels is already described on a detailed level. This review summarizes data that is currently available on their role in the central nervous system. TRP channels are involved in neurogenesis and brain development, synaptic transmission and they play a key role in the development of several neurological diseases.

TRPM4 is a Ca(2+)-activated nonselective cation channel. The channel is activated by an increase of intracellular Ca(2+) and is regulated by several factors including temperature and Pi(4,5)P2. TRPM4 allows Na(+) entry into the cell upon activation, but is completely impermeable to Ca(2+). Unlike TRPM5, its closest relative in the transient receptor potential family, TRPM4 proteins are widely expressed in the body. Currents with properties that are reminiscent of TRPM4 have been described in a variety of tissues since the advent of the patch clamp technology, but their physiological role is only beginning to be clarified with the increasing characterization of knockout mouse models for TRPM4. Furthermore, mutations in the TRPM4 gene have been associated with cardiac conduction disorders in human patients. This review aims to overview the currently available data on the functional properties of TRPM4 and the current understanding of its physiological role in healthy and diseased tissue.

TRPM4 is a calcium-activated but calcium-impermeable non-selective cation (CAN) channel. Previous studies have shown that TRPM4 is an important regulator of Ca2+-dependent changes in membrane potential in excitable and non-excitable cell types. However, its physiological significance in neurons of the central nervous system remained unclear. Here, we report that TRPM4 proteins form a CAN channel in CA1 neurons of the hippocampus and we show that TRPM4 is an essential co-activator of N-methyl-d-aspartate (NMDA) receptors (NMDAR) during the induction of long-term potentiation (LTP). Disrupting the Trpm4 gene in mice specifically eliminates NMDAR-dependent LTP, while basal synaptic transmission, short-term plasticity, and NMDAR-dependent long-term depression are unchanged. The induction of LTP in Trpm4−/− neurons was rescued by facilitating NMDA receptor activation or post-synaptic membrane depolarization. Accordingly, we obtained normal LTP in Trpm4−/− neurons in a pairing protocol, where post-synaptic depolarization was applied in parallel to pre-synaptic stimulation. Taken together, our data are consistent with a novel model of LTP induction in CA1 hippocampal neurons, in which TRPM4 is an essential player in a feed-forward loop that generates the post-synaptic membrane depolarization which is necessary to fully activate NMDA receptors during the induction of LTP but which is dispensable for the induction of long-term depression (LTD). These results have important implications for the understanding of the induction process of LTP and the development of nootropic medication.

Cardiac muscle adapts to hemodynamic stress by altering myocyte size and function, resulting in cardiac hypertrophy. Alteration in myocyte calcium homeostasis is known to be an initial signal in cardiac hypertrophy signaling. Transient receptor potential melastatin 4 protein (TRPM4) is a calcium-activated non-selective cation channel, which plays a role in regulating calcium influx and calcium-dependent cell functions in many cell types including cardiomyocytes. Selective deletion of TRPM4 from the heart muscle in mice resulted in an increased hypertrophic growth after chronic angiotensin (AngII) treatment, compared to WT mice. The enhanced hypertrophic response was also traceable by the increased expression of hypertrophy-related genes like Rcan1, ANP, and α-Actin. Intracellular calcium measurements on isolated ventricular myocytes showed significantly increased store-operated calcium entry upon AngII treatment in myocytes lacking the TRPM4 channel. Elevated intracellular calcium is a key factor in the development of pathological cardiac hypertrophy, leading to the activation of intracellular signaling pathways. In agreement with this, we observed significantly higher Rcan1 mRNA level, calcineurin enzyme activity and protein level in lysates from TRPM4-deficient mice heart compared to WT after AngII treatment. Collectively, these observations are consistent with a model in which TRPM4 is a regulator of calcium homeostasis in cardiomyocytes after AngII stimulation. TRPM4 contributes to the regulation of driving force for store-operated calcium entry and thereby the activation of the calcineurin–NFAT pathway and the development of pathological hypertrophy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-015-0501-x) contains supplementary material, which is available to authorized users.