Recent years have witnessed increased research interest in the study of the connection between TRP channels and cancer, and this has led to the discovery of tumor-related functions, such as, the regulation of tumor proliferation, differentiation, apoptosis, angiogenesis, migration, and invasion. The TRPC, TRPM, and TRPV family members are believed to be mainly involved in malignant growth and progression. The expression of TRPC6 protein in prostate cancer and the association between it and stage, grade and the androgen responsiveness of tumors have been evaluated [60]. In the TRPV family, the expressions of different TRPV channels (TRPV1, TRPV2, and TRPV6) during cancer growth and progression have been recently described [61]. High levels of TRPM1 expression were found in benign tissues, but its expression was diminished in primary melanoma [62]. TRPM8 mRNAs were found to be over-expressed in prostate tumors by RT-PCR [63,64].

TRPM7 channel is widely expressed in various tissues, including those of the brain, spleen, kidney, lung, liver, and heart [22,42]. Furthermore, its expression has been recently reported in head and neck carcinoma [64], retinoblastoma [44], breast cancer [13], and in gastric cancer [65]. The activation of TRPM7 channels in head and neck squamous carcinoma cell lines enhanced proliferation [64], whereas TRPM7 knockdown by siRNA or blockade of TRPM7 channel by Gd³⁺ or 2-APB (the latter of which has broad inhibitory effects on TRP superfamily members, including TRPM7) suppressed proliferation. Furthermore, the proliferation of human retinoblastoma cells was promoted by increasing spontaneous Ca²⁺ influx (achieved by elevating extracellular Ca²⁺ concentration) [44], and blockade of cation channels by Gd³⁺, La³⁺, LOE908, or 2-APB inhibited spontaneous Ca²⁺ influx and decreased the proliferation of retinoblastoma cells. In addition, it has been shown that TRPM7 knockdown by siRNA transfection significantly reduces Ca²⁺ influx and retards cell proliferation by delaying G1/S cell cycle progression [44]. TRPM7 channel-related proliferation has also been observed in MCF-7 human breast cancer cells [66] and AGS human gastric adenocarcinoma cells [65], as the proliferations of both were prevented by siRNA transfection induced TRPM7 knockout and by blockading TRPM7 channels with La³⁺ or 2-APB. TRPM7 channels were found in human healthy breast tissues, and the results were overexpressed in grade III breast cancer in a Ki67 proliferation marker and tumor size dependent manner [66]. TRPM7 was also found to be involved in breast cancer cell metastasis [65]. Thus, TRP channels play important roles as diagnostic and/or prognostic markers, and are targets for pharmaceutical intervention. Accordingly, further investigations are required to improve our understanding of the roles TRP channels in cancer [64].

Cell death during ischemia is often caused by increases in intracellular Ca²⁺ levels caused by massive glutamate release [67-72]. Excessive Ca²⁺ entry during ischemia causes irreversible damage to mitochondria, the cytoskeleton, and protein synthesis, and leads to cell death. Therefore, it is important that means of inhibiting excessive Ca²⁺ influx and release from internal Ca²⁺ stores are devised. Previously, Ca²⁺-permeable N-methyl-D-aspartic acid (NMDA) receptors, DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors [72], and L-type voltage-dependent Ca²⁺ channels [73] were regarded as the major pathways of Ca²⁺ entry during ischemia. Thus, blocking of these receptors and channels was considered a potential means of preventing intracellular Ca²⁺ overload. However, during clinical trials, anti-excitotoxic drugs were found to be ineffective and to have adverse effects. For example, the NMDA antagonist selfotel was administered to patients with ischemic stroke, but was not effective and tended to increase mortality, which suggested neurotoxic effects [74-77]. Therefore, researchers have been examining additional mechanisms of neuronal death, such as, the targeting of non-glutamate-related channels, including TRP channels, to induce ionic imbalance and cell death [78,79].

Interestingly, recent studies have demonstrated the pathophysiological involvement of TRPM7 in stroke. When cortical neurons were subjected to prolonged oxygen glucose deprivation (OGD), intracellular reactive oxygen/nitrogen species (ROS) levels and Ca²⁺ influx through TRPM7 channel were increased and caused cell death due to a neuronal Ca²⁺ overload [46]. However, when cortical neurons were transfected with TRPM7 siRNA, ROS-mediated activation and subsequent cell death were reduced. In addition, TRPM7 activated by OGD was found to contribute to ischemia-induced membrane depolarization, intracellular Ca²⁺ influx, and to the swelling of CA1 hippocampal neurons in brain slices taken during the acute stage [78]. In addition, it is also possible opening of TRPM7 channels induces membrane depolarizations due to Ca²⁺ influx and the removal of Mg²⁺ blocking NMDA receptors, thus exacerbating Ca²⁺ toxicity. The suppression of TRPM7 in the CA1 neurons of adult rats by injecting viral vectors containing a small hairpin RNA (shRNA) specific for TRPM7 resulted in no adverse effects on survival, neuronal or dendritic morphology, neuronal excitability, or synaptic plasticity [79]. Furthermore, TRPM7 suppression protected neuron from ischemic death after 15-min of transient global ischemia, and preserved neuronal function and morphology. These results demonstrate TRPM7 contributes to ischemic neuronal damage, and suggest that TRPM7 be viewed as a potential target for neuroprotective treatment.

Hypertension is one of the most common chronic diseases and a major risk factor of mortality and morbidity [80]. The etiology of primary (essential) hypertension is unknown but it is the most common form of the disease. However, several risk factors have been identified, including genetic, renal, metabolic, race, and environmental factors. More specifically, alterations in the intracellular levels of cations, such as, Na⁺, Ca²⁺, Mg²⁺, and K⁺, are also risk factors of hypertension [81-85].

Mg²⁺ is critically associated with the regulation of VSMC function [43], and elevated intracellular Mg²⁺ levels induce vasodilation and attenuate agonist-induced vasoconstriction, whereas depressed intracellular Mg²⁺ levels lead to hypercontractility and impaired vasorelaxation. Several studies have suggested that intracellular Mg²⁺ deficiency causes vascular dysfunction in hypertension, and that normalized intracellular Mg²⁺ levels improve vascular tone and protect against the development of hypertension [86,87].

TRPM7 has been implicated in a number of vascular pathologies, including hypertension. Angiotensin II, bradykinin (BK), and endothelin-1 regulate vascular TRPM7 acutely by inducing phosphorylation and chronically by increasing TRPM7 expression at the mRNA and protein levels [43,88-91]. Fluid flow and shear stress stimulate TRPM7 by cytosol-to-membrane translocation in VSMCs and increase the amplitude of a native TRPM7-like current [92-94]. These observations suggest TRPM7 might also act as a mechanotransducer, and that altered cellular Mg²⁺ homeostasis and abnormal VSMC function in hypertension might be related to defective TRPM7 expression/activity, which could in turn contribute to proliferation, inflammation, fibrosis, and contraction, which are important regulators of the vascular remodeling associated with high blood pressure.

VSMCs from Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) express TRPM6 and TRPM7. Basal TRPM6 expression is similar in the VSMCs of both, but basal TRPM7 expression is lower in the VSMCs of SHRs. Furthermore, this overexpression of TRPM7 was found to be associated with a significant reduction in [Mg²⁺]_i in SHR cells. In addition, the downregulation of TRPM7, but not of TRPM6, might play a role in the altered Mg²⁺ homeostasis observed in SHR VSMCs [88]. It was also reported that after exposed to shear stress, numbers of TRPM7 channels near the plasma membrane doubled in VSMCs [79]. These findings show TRPM7 is a mechanosensitive channel and that its activation induces stretch or mechanical sensing in VSMCs.

Several other TRPs, such as, TRPM4, TRPC1, and TRPC6, have been implicated in blood pressure regulation [95,96]. TRPM4 deficient mice display increased sympathetic tone and blood pressure, and increases in plasma catecholamine could explain increased mean arterial blood pressure via its well-known effect on vessel tone and cardiac output [97]. In another study, Trpc6^-/- deficient mice exhibited a basal mean arterial blood pressure elevation of ~7 mmHg [95]. This phenomenon could be explained by the compensatory overexpression of TRPC3, which has been reported in Trpc6^-/- mice [95]. On the other hand, TRPC3 is a constitutively active non-selective cation channel, and its overexpression leads to enhanced basal and agonist-induced Ca²⁺ entry into VSMCs, and eventually leads to enhanced contractility [95,98].

Guamanian amyotrophic lateral sclerosis (ALS-G) and Parkinsonism dementia (PD-G) are epidemiologically linked to an environment severely deficient in Ca²⁺ and Mg²⁺. These diseases are characterized by progressive motor neuron degeneration, and are among the most common adult onset neurodegenerative diseases [99]. TRPM7 variant with the T1482I missense mutation has been identified in ALS-G and PD-G patients. recombinant T1482I TRPM7 exhibited the same kinase catalytic activity as wild type TRPM7, but heterologously expressed T1482I TRPM7 produced functional channels that show increased sensitivity to inhibition by intracellular Mg²⁺ [40]. Because the incidence of ALS-G and PD-G has been associated with prolonged exposure to an environment severely deficient in Ca²⁺ and Mg²⁺, this variant TRPM7 allele confers a susceptible genotype in such environments. The overall effect of low Mg²⁺ is to create conditions of high oxidative stress, which is being increasingly recognized as a key player in the initiation and exacerbation of diseases, such as, ALS-PD, and is known to be associated with spinocerebellar ataxia, colorectal adenoma and carcinoma, and dyslexia [40]. However, in a recent study, Hara et al. [100] suggested that TRPM7 is not associated with ALS/PD in the Kii peninsula of Japan, which suggests familial ALS/PD is not caused by the mutation of a single gene, but that it is a complex disease involving genetic and environmental factors. Therefore, further studies are required to deduce the nature of the relationship between ALS/PD and TRPM7 channels.

Skeletal development depends on the differentiation and morphogenesis of multiple cell types to generate elements with distinct forms and functions throughout the body. It has been established TRPM7 is required for growth and skeletogenesis in zebrafish, and furthermore, TRPM7 is believed to have potential use in forward genetic approaches designed to reveal the physiological mechanisms responsible for the development of the adult form [101].