Search

Calcium homeostasis modulator 1 (CALHM1), a newly discovered voltage-dependent nonselective ion channel, has drawn attention for its role in neuronal activity and taste sensation. Its sluggish voltage-dependent activation is facilitated by lowering extracellular Ca2+ concentration ([Ca2+]e). Here, we investigated the effects of extracellular and intracellular pH (pHe and pHi) on human CALHM1. When normalized to the amplitude of the CALHM1 current (ICALHM1) under whole cell patch clamp at symmetrical pH 7.4, ICALHM1 decreased at acidic pHe or pHi, whereas it sharply increased at alkaline pHe or pHi. The effects of pH were preserved in the inside-out configuration. The voltage dependence of ICALHM1 showed leftward and rightward shifts at alkaline and acidic pHe and pHi, respectively. Site-directed mutagenesis of the water-accessible charged residues of the pore and nearby domains revealed that E17, K229, E233, D257, and E259 are nonadditively responsible for facilitation at alkaline pHi. Identification of the pHe-sensing residue was not possible because mutation of putative residues impaired membrane expression, resulting in undetectable ICALHM1. Alkaline pHe-dependent facilitation appeared gradually with depolarization, suggesting that the sensitivity to pHe might be due to H+ diffusion through the open-state CALHM1. At pHe 6.2, decreased [Ca2+]e could not recover the inhibited ICALHM1 but further augmented the increased ICALHM1 at pHe 8.6, suggesting that unidentified common residues might contribute to the [Ca2+]e and acidic pHe. This study is the first, to our knowledge, to demonstrate the remarkable pH sensitivity of CALHM1, which might contribute to the pH-dependent modulation of neuronal excitability or taste sensation. [ABSTRACT FROM AUTHOR]

Taste buds contain multiple cell types, two of which mediate transduction of specific taste qualities: Type III cells transduce sour while Type II cells transduce either sweet, or bitter or umami. In order to discern the degree of interaction between different cell types and specificity of connectivity with the afferent nerve fibers (NFs), we employed serial blockface scanning electron microscopy (sbfSEM) through five circumvallate mouse taste buds. Points of contact between Type II and Type III cells are rare and lack morphologically identifiable synapses, suggesting that interaction between these cell types does not occur via synapses. Of the 127 NFs that make synaptic contacts with taste cells in the sampling volume, ;70% (n = 91) synapse with only one taste cell while 32 fibers synapse exclusively with multiple Type II cells or multiple Type III cells. Our data do not rule out multimodal fibers innervating Type II cells of separate taste qualities. Notably, four fibers (;3%) synapse with both Type II and Type III cells, forming both mitochondrial and vesicular synapses on the different cell types. Since Type II and Type III cells transduce different taste qualities, these dual connected fibers are not consistent with a absolute labeled-line encoding system. Further, our data reveal considerable variation in both the number of synapses per cell/nerve pair and the number of innervating NFs per taste cell, both of which likely have consequences for encoding taste quality and concentration. Finally, we identify a subset of Type II cells which may represent an immature stage. [ABSTRACT FROM AUTHOR]

Highlights • Connexins, Pannexins and P2X7 in the diseased brain. • Role of Gap Junctions, Connexin hemichannels, P2X7 receptor and Pannexins in Hypoxic-Ischemic CNS. • Gap Junctions, Pannexins and P2X7 in neurological diseases. Abstract In membrane physiology, as in other fields, myths or speculations may be repeated so often and so widely that they are perceived as facts. To some extent, this has occurred with regard to gap junctions, hemichannels, pannexin channels and P2X7 (ionotropic receptors), especially concerning the interpretation of the individual role of these channels in hypoxic-ischemic CNS since these channels may be closed by the same pharmacological blockers. Significance of existing controversial data are highlighted and contradictory views from different groups are critically discussed herein. [ABSTRACT FROM AUTHOR]

Calcium homeostasis modulator 1 (CALHM1) is a calcium channel involved in the regulation of cytosolic Ca2+ levels. From a physiological point of view, the open state of CALHM1 depends not only on voltage but also on the extracellular concentration of calcium ([Ca2+]) ions. At low [Ca2+]e or depolarization, the channel is opened, allowing Ca2+ influx; however, high extracellular [Ca2+]e or hyperpolarization promote its resting state. The unique Ca2+ permeation of CALHM1 relates to the molecular events that take place in brain ischemia, such as depolarization and extracellular changes in [Ca2+]e, particularly during the reperfusion phase after the ischemic insult. In this study, we attempted to understand its role in an in vitro model of ischemia, namely oxygen and glucose deprivation, followed by reoxygenation (OGD/Reox). To this end, hippocampal slices from wild-type Calhm1+/+, Calhm1+/−, and Calhm1−/− mice were subjected to OGD/Reox. Our results point out to a neuroprotective effect when CALHM1 is partially or totally absent. Pharmacological manipulation of CALHM1 with CGP37157 reduced cell death in Calhm1+/+ slices but not in that of Calhm1−/− mice after exposure to the OGD/Reox protocol. This ionic protection was also verified by measuring reactive oxygen species production upon OGD/Reox in Calhm1+/+ and Calhm1−/− mice, resulting in a downregulation of ROS production in Calhm1−/− hippocampal slices and increased expression of HIF-1α. Taken together, we can conclude that genetic or pharmacological inhibition of CALHM1 results in a neuroprotective effect against ischemia, due to an attenuation of the neuronal calcium overload and downregulation of oxygen reactive species production.

As nontraditional model organisms with extreme physiological and morphological phenotypes, snakes are believed to possess an inferior taste system. However, the bitter taste sensation is essential to distinguish the nutritious and poisonous food resources and the genomic evidence of bitter taste in snakes is largely scarce. To explore the genetic basis of the bitter taste of snakes and characterize the evolution of bitter taste receptor genes (Tas2rs) in reptiles, we identified Tas2r genes in 19 genomes (species) corresponding to three orders of non-avian reptiles. Our results indicated contractions of Tas2r gene repertoires in snakes, however dramatic gene expansions have occurred in lizards. Phylogenetic analysis of the Tas2rs with NJ and BI methods revealed that Tas2r genes of snake species formed two clades, whereas in lizards the Tas2r genes clustered into two monophyletic clades and four large clades. Evolutionary changes (birth and death) of intact Tas2r genes in reptiles were determined by reconciliation analysis. Additionally, the taste signaling pathway calcium homeostasis modulator 1 (Calhm1) gene of snakes was putatively functional, suggesting that snakes still possess bitter taste sensation. Furthermore, Phylogenetically Independent Contrasts (PIC) analyses reviewed a significant correlation between the number of Tas2r genes and the amount of potential toxins in reptilian diets, suggesting that insectivores such as some lizards may require more Tas2rs genes than omnivorous and carnivorous reptiles.

Bitter taste perception is important for vertebrates to select food and avoid toxic substances. A large number of Tas2r genes have been identified from vertebrate species previously; however, few studies have been conducted on the Tas2r genes of Ovalentaria species that have various dietary niches and are widely distributed, ranging from the sea to freshwater environments. Several genomes of Ovalentaria species have been released recently, allowing us to study Tas2r genes in these fishes. Thus, we explored the genomes of these fishes and identified 34 Tas2r genes in 21 species, including 27 intact Tas2r genes and seven pseudogenes. The results suggest that Ovalentaria species generally carry a small repertoire of Tas2r genes. To determine the phylogenetic relationship of Tas2r genes among 21 fishes, we constructed neighbor-joining (NJ) trees. The results showed that gene duplication may not occur in these fishes. Phylogenetic independent contrast (PIC) analysis showed that the fish Tas2r gene repertoire size was not positively correlated with diet, indicating that the food swallowing behavior might reduce the importance of bitter taste sense. [ABSTRACT FROM AUTHOR]

Salt reception by taste cells is still the less understood transduction process occurring in taste buds, the peripheral sensory organs for the detection of food chemicals. Although there is evidence suggesting that the epithelial sodium channel (ENaC) works as sodium receptor, yet it is not clear how salt-detecting cells signal the relevant information to nerve endings. Taste cells responding to sweet, bitter, and umami substances release ATP as neurotransmitter through a nonvesicular mechanism. Three different channel proteins have been proposed as conduit for ATP secretion: pannexin channels, connexin hemichannels, and calcium homeostasis modulator 1 (CALHM1) channels. In heterologous expression systems, these channels mediate outwardly rectifying membrane currents with distinct biophysical and pharmacological properties. I therefore tested whether also salt-detecting taste cells were endowed with these currents. To this aim, I applied the patch-clamp techniques to single cells in isolated taste buds from rat fungiform papillae. Saltdetecting cells were functionally identified by exploiting the effect of amiloride, which induces a current response by shutting down ENaCs. I looked for the presence of outwardly rectifying currents by using appropriate voltage-clamp protocols and specific pharmacological tools. I found that indeed salt-detecting cells possessed these currents with properties consistent with the presence, at least in part, of CALHM1 channels. Unexpectedly, CALHM1-like currents in taste cells were potentiated by known blockers of pannexin, suggesting a possible inhibitory action of this protein on CALMH1. These findings indicate that communication between salt-detecting cells and nerve endings might involve ATP release by CALMH1 channels. [ABSTRACT FROM AUTHOR]

In this study, we planned to illuminate the mechanisms of the expression and function of CALHM1 in painful diabetic neuropathy (PDN). PDN rat model was constructed. The expression of CALHM1 and miR-9 in rat spinal dorsal horn neurons was detected. The correlation between the level of CALHM1 mRNA and 50 % PWT and the relationship between the expression of CALHM1 and miR-9 in rat spinal dorsal horn neurons were statistically analyzed. The effect of miR-9 and CALHM1 on each other's expression in PDN rat spinal dorsal horn neurons were tested by qRT-PCR or Western blot. The co-culture system of neurons and glias from PDN rat spinal dorsal horn was constructed. The concentration of calcium and ATP as well as the expression of P2X7 receptor regulated by CALHM1 and miR-9 in PDN rat spinal dorsal horn neurons was measured. The results showed that the expression of CALHM1 was increased in PDN rat compared with controls, while its mRNA level was negatively correlated with 50 % PWT. miR-9, which was also upregulated in the spinal dorsal horn neurons of PDN rats, was positively correlated with the expression of CALHM1. The concentration of calcium and ATP as well as the expression of P2X7 receptor in glias was also increased in PDN rats. These increases could be reverted by inhibiting CALHM1 and/or miR-9. CALHM1 is involved in miR-9-mediated ATP-P2X7 pathway between neurons and glias in PDN rat. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD), since its characterization as a precise form of dementia with its own pathological hallmarks, has captured scientists’ attention because of its complexity. The last 30 years have been filled with discoveries regarding the elusive aetiology of this disease and, thanks to advances in molecular biology and live imaging techniques, we now know that an important role is played by calcium (Ca 2+ ). Ca 2+ , as ubiquitous second messenger, regulates a vast variety of cellular processes, from neuronal excitation and communication, to muscle fibre contraction and hormone secretion, with its action spanning a temporal scale that goes from microseconds to hours. It is therefore very challenging to conceive a single hypothesis that can integrate the numerous findings on this issue with those coming from the classical fields of AD research such as amyloid-beta (Aβ) and tau pathology. In this contribution, we will focus our attention on the Ca 2+ hypothesis of AD, dissecting it, as much as possible, in its subcellular localization, where the Ca 2+ signal meets its specificity. We will also follow the temporal evolution of the Ca 2+ hypothesis, providing some of the most updated discoveries. Whenever possible, we will link the findings regarding Ca 2+ dysfunction to the other players involved in AD pathogenesis, hoping to provide a crossover body of evidence, useful to amplify the knowledge that will lead towards the discovery of an effective therapy. [ABSTRACT FROM AUTHOR]

Obesity is a major public health problem. An in-depth knowledge of the molecular mechanisms of oro-sensory detection of dietary lipids may help fight it. Humans and rodents can detect fatty acids via lipido-receptors, such as CD36 and GPR120. We studied the implication of the MAPK pathways, in particular, ERK1/2, in the gustatory detection of fatty acids. Linoleic acid, a dietary fatty acid, induced via CD36 the phosphorylation of MEK1/2-ERK1/2-ETS-like transcription factor-1 cascade, which requires Fyn-Src kinase and lipid rafts in human taste bud cells (TBCs). ERK1/2 cascade was activated by Ca2+ signaling via opening of the calcium-homeostasis modulator-1 (CALHM1) channel. Furthermore, fatty acid-evoked Ca2+ signaling and ERK1/2 phosphorylation were decreased in both human TBCs after small interfering RNA knockdown of CALHM1 channel and in TBCs from Calhm1-/- mice. Targeted knockdown of ERK1/2 by small interfering RNA or PD0325901 (MEK1/2 inhibitor) in the tongue and genetic ablation of Erk1 or Calhm1 genes impaired preference for dietary fat in mice. Lingual inhibition of ERK1/2 in healthy volunteers also decreased orogustatory sensitivity for linoleic acid. Our data demonstrate that ERK1/2-MAPK cascade is regulated by the opening of CALHM1 Ca2+ channel in TBCs to modulate orogustatory detection of dietary lipids in mice and humans. [ABSTRACT FROM AUTHOR]

Recent studies investigating the association of Calcium homeostasis modulator 1 (CALHM1) p.P86L polymorphism (rs2986017) with Alzheimer's disease (AD) are controversial. Herein, we performed a meta-analysis to investigate the association between CALHM1 rs2986017 and AD risk. Literature searches of PubMed, Alzgene, and Embase were carried out up to 24 Nov 2015. The strength of the association between rs2986017 and AD was evaluated by odds ratio (OR) and 95 % confidence interval (CI). A total of 19 studies between 2008 and 2014 comprising 8777 AD cases and 8487 controls were included. Significant association of rs2986017 with AD was found in Caucasian population in allelic model (T vs. C: OR 1.13, 95 % CI 1.02-1.26, P = 0.022), and dominant model (TT + TC vs. CC: OR 1.15, 95 % CI 1.04-1.29, P = 0.018). No significant association was found in Asian population in any genetic model. Sensitivity analysis found that Dreses-Werringloer et al.'s might affect the overall result. The current meta-analysis suggested that CALHM1 rs2986017 might be associated with increased AD risk in Caucasian, but not Asian population. [ABSTRACT FROM AUTHOR]

Calcium homeostasis modulator 1 (CALHM1), a newly discovered voltage-dependent nonselective ion channel, has drawn attention for its role in neuronal activity and taste sensation. Its sluggish voltage-dependent activation is facilitated by lowering extracellular Ca 2+ concentration ([Ca 2+ ] e ). Here, we investigated the effects of extracellular and intracellular pH (pH e and pH i ) on human CALHM1. When normalized to the amplitude of the CALHM1 current ( I CALHM1 ) under whole cell patch clamp at symmetrical pH 7.4, I CALHM1 decreased at acidic pH e or pH i , whereas it sharply increased at alkaline pH e or pH i . The effects of pH were preserved in the inside-out configuration. The voltage dependence of I CALHM1 showed leftward and rightward shifts at alkaline and acidic pH e and pH i , respectively. Site-directed mutagenesis of the water-accessible charged residues of the pore and nearby domains revealed that E17, K229, E233, D257, and E259 are nonadditively responsible for facilitation at alkaline pH i . Identification of the pH e -sensing residue was not possible because mutation of putative residues impaired membrane expression, resulting in undetectable I diffusion through the open-state CALHM1. At pH CALHM1 . Alkaline pH e -dependent facilitation appeared gradually with depolarization, suggesting that the sensitivity to pH e might be due to H + diffusion through the open-state CALHM1. At pH e 6.2, decreased [Ca 2+ ] e could not recover the inhibited I CALHM1 . This study is the first, to our knowledge, to demonstrate the remarkable pH sensitivity of CALHM1, which might contribute to the pH-dependent modulation of neuronal excitability or taste sensation.I CALHM1 at pH e 8.6, suggesting that unidentified common residues might contribute to the [Ca 2+ ] e and acidic pH e . This study is the first, to our knowledge, to demonstrate the remarkable pH sensitivity of CALHM1, which might contribute to the pH-dependent modulation of neuronal excitability or taste sensation.

The sensitivity of taste in mammals varies due to quantitative and qualitative differences in the structure of the taste perception organs. Gustatory perception is made possible by the peripheral chemosensory organs, i.e., the taste buds, which are distributed in the epithelium of the taste papillae of the palate, tongue, epiglottis, throat and larynx. Each taste bud consists of a community of ~100 cells that process and integrate taste information with metabolic needs. Mammalian taste buds are contained in circumvallate, fungiform and foliate papillae and react to sweet, salty, sour, bitter and umami stimuli. The sensitivity of the taste buds for individual taste stimuli varies extensively and depends on the type of papillae and the part of the oral cavity in which they are located. There are at least three different cell types found in mammalian taste buds: type I cells, receptor (type II) cells and presynaptic (type III) cells. This review focuses on the biophysiological mechanisms of action of the various taste stimuli in humans. Currently, the best-characterized proteins are the receptors (GPCR). In addition, the activation of bitter, sweet and umami tastes are relatively well known, but the activation of salty and sour tastes has yet to be clearly explained. [ABSTRACT FROM AUTHOR]

Taste compounds detected by G protein-coupled receptors on the apical surface of Type 2 taste cells initiate an intracellular molecular cascade culminating in the release of ATP . It has been suggested that this ATP release is accomplished by pannexin 1 (PANX1). However, we report here that PANX1 knockout mice do not differ from wild-type controls in response to representative taste solutions, measured using 5-s brief-access tests or 48-h two-bottle choice tests. This implies that PANX1 is unnecessary for taste detection and consequently that ATP release from Type 2 taste cells does not require PANX1. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is characterized by amyloid-ß (Aβ) peptide accumulation in the brain. CALHM1, a cell-surface Ca²+ channel expressed in brain neurons, has anti-amyloidogenic properties in cell cultures. Here, we show that CALHM1 controls Aβ levels in vivo in the mouse brain through a previously unrecognized mechanism of regulation of Aβ clearance. Using pharmacological and genetic approaches in cell lines, we found that CALHM1 ion permeability and extracellular Ca²+ were required for the Aβ-lowering effect of CALHM1. Aβ level reduction by CALHM1 could be explained by an increase in extracellular Aβ degradation by insulin-degrading enzyme (IDE), extracellular secretion of which was strongly potentiated by CALHM1 activation. Importantly, Calhml knockout in mice reduced IDE enzymatic activity in the brain, and increased endogenous Aβ concentrations by up to ~50% in both the whole brain and primary neurons. Thus, CALHM1 controls Aβ levels in cell lines and in vivo by facilitating neuronal and Ca²+-dependent degradation of extracellular Aβ by IDE. This work identifies CALHM1 ion channel as a potential target for promoting amyloid clearance in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Stimulation of Type II taste receptor cells (TRCs) with T1R taste receptors causes sweet or umami taste, whereas T2Rs elicit bitter taste. Type II TRCs contain the calcium channel, calcium homeostasis modulator protein 1 (CALHM1), which releases adenosine triphosphate (ATP) transmitter to taste fibers. We have previously demonstrated with chorda tympani nerve recordings and two-bottle preference (TBP) tests that mice with genetically deleted Calhm1 (knockout [KO]) have severely impaired perception of sweet, bitter, and umami compounds, whereas their sour and salty tasting ability is unaltered. Here, we present data from KO mice of effects on glossopharyngeal (NG) nerve responses, TBP, food intake, body weight, and life span. KO mice have no NG response to sweet and a suppressed response to bitter compared with control (wild-type [WT]) mice. KO mice showed some NG response to umami, suggesting that umami taste involves both CALHM1- and non-CALHM1modulated signals. NG responses to sour and salty were not significantly different between KO and WT mice. Behavioral data conformed in general with the NG data. Adult KO mice consumed less food, weighed significantly less, and lived almost a year longer than WT mice. Taken together, these data demonstrate that sweet taste majorly influences food intake, body weight, and life span. [ABSTRACT FROM AUTHOR]

Adenosine 5′-triphosphate (ATP) is released as a genuine co-transmitter, or as a principal purinergic neurotransmitter, in an exocytotic and non-exocytotic manner. It activates ionotropic (P2X) and metabotropic (P2Y) receptors which mediate a plethora of functions in the brain. In particular, P2X7 receptor (P2X7R) are expressed in all brain cells and its activation can form a large pore allowing the passage of organic cations, the leakage of metabolites of up to 900 Da and the release of ATP itself. In turn, pannexins (Panx) are a family of proteins forming hemichannels that can release ATP. In this review, we summarize the progress in the understanding of the mechanisms of ATP release both in physiological and pathophysiological stages. We also provide data suggesting that P2X7R and pannexin 1 (Panx1) may form a large pore in cortical neurons as assessed by electrophysiology. Finally, the participation of calcium homeostasis modulator 1 is also suggested, another non-selective ion channel that can release ATP, and that could play a role in ischemic events, together with P2X7 and Panx1 during excitotoxicity by ATP. [ABSTRACT FROM AUTHOR]

Calcium homeostasis modulator 1 (CALHM1) is a Ca2+ channel controlling neuronal excitability and potentially involved in the pathogenesis of Alzheimer's disease (AD). Although strong evidence indicates that CALHM1 is required for neuronal electrical activity, its role in intracellular Ca2+ signaling remains unknown. In the present study, we show that in hippocampal HT-22 cells, CALHM1 expression led to a robust and relatively selective activation of the Ca2+-sensing kinases ERK1/2. CALHM1 also triggered activation of MEK1/2, the upstream ERK1/2-activating kinases, and of RSK1/2/3 and MSK1, two downstream effectors of ERK1/2 signaling. CALHM1-mediated activation of ERK1/2 signaling was controlled by the small GTPase Ras. Pharmacological inhibition of CALHM1 permeability using Ruthenium Red, Zn2+, and Gd3+, or expression of the CALHM1 N140A and W114A mutants, which are deficient in mediating Ca2+ influx, prevented the effect of CALHM1 on the MEK, ERK, RSK and MSK signaling cascade, demonstrating that CALHM1 controlled this pathway via its channel properties. Importantly, expression of CALHM1 bearing the natural P86L polymorphism, which leads to a partial loss of CALHM1 function and is associated with an earlier age at onset in AD patients, showed reduced activation of ERK1/2, RSK1/2/3, and MSK1. In line with these results obtained in transfected cells, primary cerebral neurons isolated from Calhm1 knockout mice showed significant impairments in the activation of MEK, ERK, RSK and MSK signaling. The present study identifies a previously uncharacterized mechanism of control of Ca2+-dependent ERK1/2 signaling in neurons, and further establishes CALHM1 as a critical ion channel for neuronal signaling and function. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a complex neurodegenerative disorder characterized by memory and cognitive impairment and is the leading cause of dementia in the elderly. The aim of our study was to examine the polymorphic DNA markers CCR2 (+190 G/A), CCR5Δ32, TNF-α (-308 G/A), TNF-α (-863 C/A) and CALHM1 (+394 C/T) to determine the relationship between these polymorphisms and the risk of late onset Alzheimer's disease in the population of Eastern Azerbaijan of Iran. A total of 160 patient samples and 163 healthy controls were genotyped by PCR-RFLP and the results confirmed using bidirectional sequencing. Statistical analysis of obtained data revealed non-significant difference between frequency of CCR5Δ32 in case and control groups. The same result was observed for TNF-α (-863 C/A) genotype and allele frequencies. Contrary to above results, significant differences were detected in frequency of TNF-α (-308 G/A) and CCR2-64I genotypes between the cases and healthy controls. A weak significant difference observed between allele and genotype frequencies of rs2986017 in CALHM1 (+394 C/T; P86L) in patient and control samples. It can be concluded that the T allele of P86L variant in CALHM1 & +190 G/A allele of CCR2 have a protective role against abnormal clinical features of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ℇ4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the ℇ4 allele of the APOE gene. [ABSTRACT FROM AUTHOR]

Recent large-scale genetic studies of late-onset Alzheimer's disease have identified risk variants in CALHM1, GAB2, and SORL1. The mechanisms by which these genes might modulate risk are not definitively known. CALHM1 and SORL1 may alter amyloid-β (Aβ) levels and GAB2 may influence phosphorylation of the tau protein. In this study we have analyzed disease associated genetic variants in each of these genes for association with cerebrospinal fluid (CSF) Aβ or tau levels in 602 samples from two independent CSF series. We failed to detect association between CSF Aβ42 levels and single nucleotide polymorphisms in SORL1 despite substantial statistical power to detect association. While we also failed to detect association between variants in GAB2 and CSF tau levels, power to detect this association was limited. Finally, our data suggest that the minor allele of rs2986017, in CALHM1, is marginally associated with CSF Aβ42 levels. This association is consistent with previous reports that this non-synonymous coding substitution results in increased Aβ levels in vitro and provides support for an Aβ-related mechanism for modulating risk for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

CALHM1 gene coding non-synonymous SNP P86L (rs2986017) was reported to increase the risk of Alzheimer's disease (AD) in a recent study. We have investigated this genetic variant in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP marker. By applying a recessive model, we observed weak evidence of an association between P86L mutation and late-onset AD (LOAD) susceptibility in our case-control study (OR =1.38 C.I. = [1.01–1.89]). Meta-analysis of available studies also supports a recessive model for CALHM1 P86L variant and provides evidence of between study heterogeneity. Importantly, we found that adjusted mean age at AD onset in P86L homozygous LOAD patients was significantly earlier that in the rest of patients (77.01 ± 6.1 for P86L homozygous carriers versus 79.0 ± 6.0 for the rest of patients, p=0.002). We concluded that the CALMH1 gene may contribute to AD risk in our study population. The observed genetic model (recessive) and the estimated magnitude of the effect both imply that virtually all studies performed to date were markedly underpowered to detect this effect and underscore the importance of follow up, replication, and meta-analyses of promising genetic signals. [ABSTRACT FROM AUTHOR]

We conducted a case-control study to determine the prevalence of the CALHM1 P86L polymorphism (rs2986017) in patients with Alzheimer's disease (AD) in the Chinese population of mainland China, and also to clarify whether this polymorphism is a risk factor for AD. Fourteen heterozygous P86L carriers were identified among 198 AD patients. One control subject was also found to be a P86L heterozygous carrier. The allelic frequencies of the AD patients and control subjects were found to be significantly different. Our study indicates that the CALHM1-P86L polymorphism is associated with AD in the ethnic Chinese Han. [ABSTRACT FROM AUTHOR]

Abstract: The novel Ca2+ channel CALHM1 (Calcium Homeostasis Modulator 1) generates cytosolic Ca2+ transients ([Ca2+]c) that regulate the production of amyloid beta (Aβ). Its mutated channel P86L-CALHM1 has been associated to Alzheimer’s disease (AD). Using cytosolic- and mitochondrial-targeted aequorins, we have investigated here whether mitochondria sense with similar or different kinetics the Ca2+ entering into Hela cells and the Ca2+ released from the endoplasmic reticulum (ER), in control and in cells transfected with CALHM1 and P86L-CALHM1. We have shown that mitochondria sense Ca2+ entry in the three cell types; however, the [Ca2+]c and mitochondrial Ca2+ transients [Ca2+]m had substantially slower kinetics in cells expressing P86L-CALHM1. Mitochondria also sensed the ER Ca2+ released by histamine, but in CALHM1 and P86L-CALHM1 cells the kinetics was faster than that of control cells. Data are compatible with the idea that mutated CALHM1 may cause mitochondrial Ca2+ overload, suggesting how these cells may become more vulnerable to apoptotic stimuli. [Copyright &y& Elsevier]

Calcium homeostasis modulator 1 (CALHM1) is a voltage- and Ca 2+ -gated ATP channel that plays an important role in neuronal signaling. However, as the previously reported CALHM structures are all in the ATP-conducting state, the gating mechanism of ATP permeation is still elusive. Here, we report cryo-EM reconstructions of two Danio rerio CALHM1 heptamers with ordered or flexible long C-terminal helices at resolutions of 3.2 Å and 2.9 Å, respectively, and one D. rerio CALHM1 octamer with flexible long C-terminal helices at a resolution of 3.5 Å. Structural analysis shows that the heptameric CALHM1s are in an ATP-nonconducting state with a central pore diameter of approximately 6.6 Å. Compared with those inside the octameric CALHM1, the N-helix inside the heptameric CALHM1 is in the "down" position to avoid steric clashing with the adjacent TM1 helix. Molecular dynamics simulations show that as the N-helix moves from the "down" position to the "up" position, the pore size of ATP molecule permeation increases significantly. Our results provide important information for elucidating the mechanism of ATP molecule permeation in the CALHM1 channel., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Taste buds consist of specialized epithelial cells which detect particular tastants and synapse onto the afferent taste nerve innervating the endorgan. The nature of the neurotransmitter released by taste cells onto the nerve fiber was enigmatic early in this century although neurotransmitters for other sensory receptor cell types, e.g. hair cells, photoreceptors, was known for at least a decade. A 1999 paper by Burnstock and co-workers (Bo et al., 1999) showing the presence of P2X receptors on the afferent nerves served as a springboard for research that ultimately led to the discovery of ATP as the crucial neurotransmitter in the taste system (Finger et al., 2005). Subsequent work showed that a subpopulation of taste cells utilize a unique release channel, CALHM1/3, to release ATP in a voltage-dependent manner. Despite these advances, several aspects of purinergic transmission in this system remain to be elucidated. [ABSTRACT FROM AUTHOR]