One Single Nucleotide Polymorphism of the TRPM2 Channel Gene Identified as a Risk Factor in Bipolar Disorder Associates With Autism Spectrum Disorder in a Japanese Population

Abstract

The transient receptor potential melastatin 2 (TRPM2) is a non-specific cation channel, resulting in Ca2+ influx at warm temperatures from 34 °C to 47 °C, thus including the body temperature range in mammals. TRPM2 channels are activated by β-NAD+, ADP-ribose (ADPR), cyclic ADPR, and 2′-deoxyadenosine 5′-diphosphoribose. It has been shown that TRPM2 cation channels and CD38, a type II or type III transmembrane protein with ADP-ribosyl cyclase activity, simultaneously play a role in heat-sensitive and NAD+ metabolite-dependent intracellular free Ca2+ concentration increases in hypothalamic oxytocinergic neurons. Subsequently, oxytocin (OT) is released to the brain. Impairment of OT release may induce social amnesia, one of the core symptoms of autism spectrum disorder (ASD). The risk of single nucleotide polymorphisms (SNPs) and variants of TRPM2 have been reported in bipolar disorder, but not in ASD. Therefore, it is reasonable to examine whether SNPs or haplotypes in TRPM2 are associated with ASD. Here, we report a case-control study with 147 ASD patients and 150 unselected volunteers at Kanazawa University Hospital in Japan. The sequence-specific primer-polymerase chain reaction method together with fluorescence correlation spectroscopy was applied. Of 14 SNPs examined, one SNP (rs933151) displayed a significant p-value (OR = 0.1798, 95% CI = 0.039, 0.83; Fisher’s exact test; p = 0.0196). The present research data suggest that rs93315, identified as a risk factor for bipolar disorder, is a possible association factor for ASD.

Roles of TRPM channels in glioma

“… 130 Furthermore, abnormal TRPM2 function appears to be associated with psychiatric and neurological disorders, such as stress depression, epilepsy, ischemic brain damage, and glioma invasion. 131 Moreover, TRPM2-S and TRPM2-AS are also closely associated with malignant tumors such as gliomas. 132 TRPM2-S is an isomer of TRPM2, which activates the ERAD system to ubiquitinate TRPM2 and inhibit TRPM2 activity by interacting with TRPM2 located at the cytoplasmic membrane.…”

Dual Oxytocin Receptor-G Protein Signaling in the Autoregulation of Activities of Oxytocin Neurons

“…Phosphorylation of specific residues of NaV1.7 by pERK1 can modulate NaV1.7 gating features [139]. Moreover, TRP melastatin 2 channel plays a role in heat-sensitive and NAD + metabolite-dependent intracellular free Ca 2+ concentration increases in OT neurons [140]. In addition, other channels may also contribute to the excitability of OT neurons through different mechanisms, such as N-terminal-truncated variant of TRP vanilloid type-1, epithelial Na + channels, and labile Ca 2+ -permeable GluA1 receptors [7, 10].…”

Ionic Channels as Potential Targets for the Treatment of Autism Spectrum Disorder: A Review

“…The physiological activity of TRPM2 and TRPM7 in the brain has recently been identified in neuronal structures, astrocytes, and glial cells as being primordial for cognitive function, as well as for hormonal modulation and embryonic neurogenesis [ 97 ]. Despite the mechanisms being still poorly understood, TRPM2 and TRPM7 channels likely contribute to the improvement of ASD social deficiencies.…”

“…Despite the mechanisms being still poorly understood, TRPM2 and TRPM7 channels likely contribute to the improvement of ASD social deficiencies. The channels can be activated by nicotinamide and adenine beta dinucleotides (β-NAD), and ADP-ribose, and by increased body temperature (34 to 47°C), regulating the release of oxytocin (OT) in hypothalamic oxytocinergic neurons, in a mechanism dependent on free intracellular calcium [ 97 , 98 ]. Decreased OT release may increase the individual's predisposition to-wards social amnesia, a symptom also characteristic of ASD.…”