Reinhold Penner

• MD, PhD
• Managing Director at The Queen's Medical Center

Background Pyroptosis, a novel form of programmed cell death, has been implicated in neurodegeneration diseases. However, its role in status epilepticus (SE)—a condition characterized by prolonged or repeated seizures—remains inadequately understood. Methods SE were induced by intraperitoneal injection of pilocarpine (PILO). Neuronal excitability...

Using genetically engineered mice and cell lines derived from genetically engineered mice we show that depletion of ER delimited Ca ²⁺ stores activates heteromeric Ca ²⁺ entry (SOCE) channels formed obligatorily, but not exclusively by Orai1 molecules. Comparison of Orai-dependent Ca ²⁺ entries revealed Orai1 to be dominant when compared to Orai2 a...

Cannabinoids are a major class of compounds produced by the plant Cannabis sativa. Previous work has demonstrated that the main cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC) can have some beneficial effects on pain, inflammation, epilepsy, and chemotherapy-induced nausea and vomiting. While CBD and THC represent the two major plant...

Cannabidiol (CBD) is thought to have multiple biological effects, including the ability to attenuate inflammatory processes. Cannabigerols (CBGA and its decarboxylated CBG molecule) have pharmacological profiles similar to CBD. The endocannabinoid system has recently emerged to contribute to kidney disease, however, the therapeutic properties of ca...

Cannabis sativa has long been known to affect numerous biological activities. Although plant extracts, purified cannabinoids, or synthetic cannabinoid analogs have shown therapeutic potential in pain, inflammation, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting, the underlying mechanisms of action remai...

TRPM7 belongs to the Transient Receptor Potential Melastatin family of ion channels and is a divalent cation-conducting ion channel fused with a functional kinase. TRPM7 plays a key role in a variety of diseases, including neuronal death in ischemia, cancer, cardiac atrial fibrillation, malaria invasion. TRPM7 is aberrantly over-expressed in lung,...

Transient receptor potential melastatin type 2 (TRPM2) is a cation channel activated by free intracellular ADP-ribose and reactive oxygen species. TRPM2 signaling has been linked to the pathophysiology of CNS disorders such as neuropathic pain, bipolar disorder and Alzheimer's disease. In this manuscript, we describe the discovery of JNJ-28583113,...

The melastatin-related transient receptor potential member 7 (TRPM7) is a unique fusion protein with both ion channel function and enzymatic α-kinase activity. TRPM7 is essential for cellular systemic magnesium homeostasis and early embryogenesis; it promotes calcium transport during global brain ischemia and emerges as a key player in cancer growt...

Betel nut consumption has significant implications for the public health globally, as the wide-spread habit of Areca chewing throughout Asia and the Pacific is associated with a high prevalence of oral carcinoma and other diseases. Despite a clear causal association of betel nut chewing and oral mucosal diseases, the biological mechanisms that link...

Background: Magnesium (Mg2+) is an essential cation implicated in carcinogenesis, solid tumor progression and metastatic potential. The Transient Receptor Potential Melastatin Member 7 (TRPM7) is a divalent ion channel involved in cellular and systemic Mg2+ homeostasis. Abnormal expression of TRPM7 is found in numerous cancers, including colon, im...

TRPM2 is a Ca²⁺-permeable, nonselective cation channel that plays a role in oxidant-induced cell death, insulin secretion, and cytokine release. Few TRPM2 inhibitors have been reported, which hampers the validation of TRPM2 as a drug target. While screening our in-house marine-derived chemical library, we identified scalaradial and 12-deacetylscala...

TRPM7 is a member of the Transient-Receptor-Potential Melastatin ion channel family. TRPM7 is a unique fusion protein of an ion channel and an α-kinase. Although mammalian TRPM7 is well characterized biophysically and its pivotal role in cancer, ischemia and cardiovascular disease is becoming increasingly evident, the study of TRPM7 in mouse models...

CNNM2 is associated with the regulation of serum Mg concentration, and when mutated, with severe familial hypomagnesemia. The function and cellular localization of CNNM2 and its isomorphs (Iso) remain controversial. The objective of this work was to examine the following: (1) the transcription-responsiveness of CNNM2 to Mg starvation, (2) the cellu...

TRPM2 is a calcium‐permeable non‐selective cation channel that is activated, in a synergistic manner, by both intracellular adenosine diphosphate ribose (ADPR) and calcium. It is also activated indirectly by reactive oxygen nitrogen species (ROS/NOS) due to increased ADPR production during oxidative/nitrosative stress. TRPM2 is primarily expressed...

Key points: The Mg(2+) and Ca(2+) conducting transient receptor potential melastatin 7 (TRPM7) channel-enzyme (chanzyme) has been implicated in immune cell function. Mice heterozygous for a TRPM7 kinase deletion are hyperallergic, while mice with a single point mutation at amino acid 1648, silencing kinase activity, are not. As mast cell mediators...

Kv1.3 potassium channels are promising pharmaceutical targets for treating immune diseases as they modulate Ca(2+) signaling in T cells by regulating the membrane potential and with it the driving force for Ca(2+) influx. The anti-mycobacterial drug clofazimine has been demonstrated to attenuate antigen-induced Ca(2+) oscillations, suppress cytokin...

Small-conductance, Ca2+ activated K+ channels (SK channels) are expressed at high levels in brain regions responsible for learning and memory. In the current study we characterized the contribution of SK2 channels to synaptic plasticity and to different phases of hippocampal memory formation. Selective SK2 antisense-treatment facilitated basal syna...

Intracellular levels of the divalent cations Ca2+ and Mg2+ are important regulators of cell cycle and proliferation. However, the precise mechanisms by which they are regulated in cancer remain incompletely understood. The channel kinases TRPM6 and TRPM7 are gatekeepers of human Ca2+/Mg2+ metabolism. Here, we investigated the human neuroblastoma ce...

Deviations from physiological pH (∼pH 7.2) as well as altered Ca(2+) signaling play important roles in immune disease and cancer. One of the most ubiquitous pathways for cellular Ca(2+) influx is the store-operated Ca(2+) entry (SOCE) or Ca(2+) release-activated Ca(2+) current (ICRAC), which is activated upon depletion of intracellular Ca(2+) store...

TRPM2 is the second member of the transient receptor potential melastatin-related (TRPM) family of cation channels. The protein is widely expressed including in the brain, immune system, endocrine cells, and endothelia. It embodies both ion channel functionality and enzymatic ADP-ribose (ADPr) hydrolase activity. TRPM2 is a Ca(2+)-permeable nonsele...

The present invention provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein each of W, Q, R1, R2, R3, R4, R5, m, and n is as defined herein, pharmaceutically acceptable compositions thereof, and methods of using the same.

The transient receptor potential melastatin member 7 (TRPM7) and member 6 (TRPM6) are divalent cation channel kinases essential for magnesium (Mg2+) homeostasis in vertebrates. It remains unclear how TRPM6 affects divalent cation transport and whether this involves functional homomeric TRPM6 plasma membrane channels or heteromeric channel assemblie...

Airway inflammation and asthma have been linked to oxidative stress and the melastatin-related transient receptor potential cation channel, member 2 (TRPM2), which can be activated by reactive oxygen species (ROS), has emerged as a potential therapeutic target for inflammatory diseases. Using TRPM2 deficient (TRPM2-/-) mice, we investigated whether...

Transient receptor potential melastatin 7 (TRPM7) is a divalent-selective cation channel fused to an atypical α-kinase. TRPM7 is a key regulator of cell growth and proliferation, processes accompanied by mandatory cell volume changes. Osmolarity-induced cell volume alterations regulate TRPM7 through molecular crowding of solutes that affect channel...

Key points Stromal cell‐interaction molecule (STIM) 2 senses Ca ²⁺ levels in the endoplasmic reticulum and activates Ca ²⁺ channels in the plasma membrane upon store depletion. Here we report that STIM2 is preferentially activated by low agonist concentrations that cause mild reductions in endoplasmic reticulum Ca ²⁺ levels. This shows that store‐o...

Members of the Orai family are highly selective calcium ion channels that play an important role in store-operated calcium entry. Among the three known Orai isoforms, Orai3 has gained increased attention, notably for its emerging role in cancer. We recently demonstrated that Orai3 channels are over-expressed in breast cancer (BC) biopsies, and invo...

Transient receptor potential melastatin 7 (TRPM7) channels represent the major magnesium-uptake mechanism in mammalian cells and are key regulators of cell growth and proliferation. They are expressed abundantly in a variety of human carcinoma cells controlling survival, growth, and migration. These characteristics are the basis for recent interest...

Chemokines induce calcium (Ca(2+)) signaling and chemotaxis in dendritic cells (DCs), but the molecular players involved in shaping intracellular Ca(2+) changes remain to be characterized. Using siRNA and knockout mice, we show that in addition to inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) release and store-operated Ca(2+) entry (SOCE), t...

Ca(2+) signaling includes store-operated Ca(2+) entry (SOCE) following depletion of endoplasmic reticulum (ER) Ca(2+) stores. On store depletion, the ER Ca(2+) sensor STIM1 activates Orai1, the pore-forming unit of Ca(2+)-release-activated Ca(2+) (CRAC) channels. Here, we show that Orai1 is regulated by serum- and glucocorticoid-inducible kinase 1...

The transient potential receptor melastatin-2 (TRPM2) channel has emerged as an important Ca(2+) signalling mechanism in a variety of cells, contributing to cellular functions that include cytokine production, insulin release, cell motility and cell death. Its ability to respond to reactive oxygen species has made TRPM2 a potential therapeutic targ...

Store-operated Ca(2+) entry is controlled by the interaction of stromal interaction molecules (STIMs) acting as endoplasmic reticulum ER Ca(2+) sensors with calcium release-activated calcium (CRAC) channels (CRACM1/2/3 or Orai1/2/3) in the plasma membrane. Here, we report structural requirements of STIM1-mediated activation of CRACM1 and CRACM3 usi...

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) play a role in both innate immunity as well as cellular injury. H2O2 induces changes in intracellular calcium ([Ca(2+)]i) in many cell types and this seems to be at least partially mediated by transient receptor potential melastatin 2 (TRPM2) in cells that express this channel. Here we...

Insulin secretion in β-pancreatic cells due to glucose stimulation requires the coordinated alteration of cellular ion concentrations and a substantial membrane depolarization to enable insulin vesicle fusion with the cellular membrane. The cornerstones of this cascade are well characterized, yet current knowledge argues for the involvement of addi...

Chemokines induce Ca2+ signaling and chemotaxis in dendritic cells (DCs) but the molecular players involved in shaping the changes in intracellular Ca2+ remain to be characterized. Using siRNA and knock-out mice, we show that in addition to IP3-mediated Ca2+ release and store-operated Ca2+ entry the transient receptor potential melastatin 2 (TRPM2)...

TRPM7 is a bi-functional protein where an ion channel domain is fused with an atypical α-kinase domain. Impairment of the kinase domain leads to hypomagnesemia and sensitization to allergic reactions. We here investigate whether TRPM7 is involved in receptor-stimulated peritoneal mast cell degranulation and histamine release. Using the whole-cell p...

TRPM7 is a ubiquitously expressed and constitutively active divalent cation channel essential for cell survival and proliferation because it provides a mechanism for Mg2+ entry. This makes the channel an attractive target for proliferative diseases. In keeping with its role in Mg2+ homeostasis, TRPM7 is inhibited by intracellular Mg2+ and Mg-ATP. T...

TRPM2 is a calcium-permeable non-selective cation channel expressed in the plasma membrane and in lysosomes that is critically involved in aggravating reactive oxygen species (ROS)-induced inflammatory processes and has been implicated in cell death. TRPM2 is gated by ADP-ribose (ADPR) and modulated by physiological processes that produce peroxide,...

Store-operated calcium entry (SOCE) or calcium release-activated calcium current (I(CRAC)) is a critical pathway to replenish intracellular calcium stores, and plays indispensable roles in cellular functions such as antigen-induced T lymphocyte activation. Despite the importance of I(CRAC) in cellular functions, lack of potent and specific inhibito...

The store-operated, calcium release-activated calcium current I(CRAC) is activated by the depletion of inositol 1,4,5-trisphosphate (IP(3))-sensitive stores. The significantly different dose-response relationships of IP(3)-mediated Ca(2+) release and CRAC channel activation indicate that I(CRAC) is activated by a functionally, and possibly physical...

TRPM2 is a Ca2+-permeable cation channel that is specifically activated by adenosine diphosphoribose (ADPR). Channel activation in the plasma membrane leads to Ca2+ influx and has been linked to apoptotic mechanisms. The primary agonist, ADPR, is produced both extra- and intracellularly and causes increases in intracellular calcium concentration ([...

Clofazimine does not affect the enzymatic activity of calcineurin in vitro. (A) Clofazimine does not inhibit the protein phosphatase activity of calcineurin in vitro. 20 mM p-nitrophenylphosphate was incubated with purified recombinant calcineurin A/B and calmodulin in the presence of 1 mM calcium or 5 mM EGTA at 30°C. The progress of the reaction...

Effects of clofazimine on AP-1 luciferase reporter gene and the nuclear translocation of NFAT in response to ionomycin treatment. (A) Dose-dependent enhancement of the AP-1 luciferase reporter gene by CsA (n = 6). (B) Clofazimine inhibits EGFP-NFATc3 nuclear translocation in Jurkat T cells stimulated by 1 µM ionomycin. Images were taken 30 minutes...

Clofazimine alters calcium oscillation patterns in Jurkat T cells without affecting reconstituted ICRAC in HEK293 cells. (A, B) Time-dependent increase in the population of cells that are sensitive to clofazimine. Jurkat T cells were incubated with clofazimine for varied lengths of time before 1 µM TG was added. Images were taken 30 min after 2 mM...

Knockdown of Kv1.3 did not affect the sensitivity of the IL-2 luciferase reporter to CsA. The IC50 for control EGFP-siRNA lentiviral transduced Jurkat T cells was 2.5±0.6 nM, and that for Kv1.3 lentiviral 4 transduced T cells was 2.6±0.7 nM (n = 6). (0.00 MB TIF)

Supporting Materials and Methods (0.10 MB DOC)

Effect of 10 µM clofazimine on heterologous Kv1.1, Kv1.2 Kv1.5 and Kv3.1. (A) Average time course of mouse Kv1.1 currents stably expressed in L929 cells. Control cells (closed circles, n = 5, no application) and cells superfused with 10 µM clofazimine added to the standard extracellular solution (open circles, n = 6) as indicated by the black bar....

Inhibition of Kv channels by 10 µM clofazimine assessed at 0 mV (red bars) or +80 mV (black bars). Same cells as in Fig. 3D and Fig. S4 were used. Note the increased inhibitory effect at 0 mV for all Kv channels displayed except Kv1.3. (0.19 MB TIF)

Effects of clofazimine on mouse TCR-mediated IL-2 production and mixed lymphocyte reaction in murine T cells. (A) Dose response of IL-2 production from anti-CD3/anti-CD28-stimulated mouse primary T cells to different concentrations of clofazimine (n = 3). (B) Biphasic effects of clofazimine on mouse mixed lymphocyte reaction (n = 3). (0.00 MB TIF)

Effects of Psora-4 on calcium influx and the activation of different reporter genes in Jurkat T cells. (A) Calcium influx in Jurkat T cells was inhibited by 10 µM psora-4 in a heterogeneous fashion. Psora-4 was added 5 minutes before stimulation with 1 µM TG. Representative images were taken 30 minutes after 2 mM calcium was added. The color gradie...

The molecular characterization of the genes encoding the transient receptor potential (TRP) cation channels found in Drosophila photoreceptors gave rise to a systematic cloning strategy for mammalian isoforms. Using expressed sequence tag (EST) and genomic database searches, at least 20 new mammalian TRP-related genes have been cloned and the resul...

Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca(2+)-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H(2)O(2)) evokes Ca(2+) influx through TRPM2 t...

2-Aminoethoxydiphenyl borate (2-APB) has emerged as a useful pharmacological tool in the study of store-operated Ca(2+) entry (SOCE). It has been shown to potentiate store-operated Ca(2+) release-activated Ca(2+) (CRAC) currents at low micromolar concentrations and to inhibit them at higher concentrations. Initial experiments with the three CRAC ch...

The Ca(2+)-permeable TRPM2 channel is a dual function protein that is activated by intracellular ADPR through its enzymatic pyrophosphatase domain with Ca(2+) acting as a co-factor. Other TRPM2 regulators include cADPR, NAADP and H(2)O(2), which synergize with ADPR to potentiate TRPM2 activation. Although TRPM2 has been thoroughly characterized in...

STIM1 and CRACM1 (or Orai1) are essential molecular components mediating store-operated Ca2+ entry (SOCE) and Ca2+ release-activated Ca2+ (CRAC) currents. Although STIM1 acts as a luminal Ca2+ sensor in the endoplasmic reticulum (ER), the function of STIM2 remains unclear. Here we reveal that STIM2 has two distinct modes of activating CRAC channels...

The Kv1.3 potassium channel plays an essential role in effector memory T cells and has been implicated in several important autoimmune diseases including multiple sclerosis, psoriasis and type 1 diabetes. A number of potent small molecule inhibitors of Kv1.3 channel have been reported, some of which were found to be effective in various animal mode...

Microglia are the main immunocompetent cells of the mammalian central nervous system (CNS). Activation of cultured microglial cells and subsequent release of nitric oxide and cytokines critically depends on intracellular calcium levels. Since microglia undergo dramatic morphological, biochemical and electrophysiological changes in response to patho...

TRPM2 is a calcium-permeable nonselective cation channel that is opened by the binding of ADP-ribose (ADPR) to a C-terminal nudix domain. Channel activity is further regulated by several cytosolic factors, including cyclic ADPR (cADPR), nicotinamide adenine dinucleotide phosphate (NAADP), Ca(2+) and calmodulin (CaM), and adenosine monophosphate (AM...

STIM1 in the endoplasmic reticulum and CRACM1 in the plasma membrane are essential molecular components for controlling the store-operated CRAC current. CRACM1 proteins multimerize and bind STIM1, and the combined overexpression of STIM1 and CRACM1 reconstitutes amplified CRAC currents. Mutations in CRACM1 determine the selectivity of CRAC currents...

Calcium signaling is a central mechanism for numerous cellular functions and particularly relevant for immune cell proliferation. However, the role of calcium influx in mitotic cell cycle progression is largely unknown. We here report that proliferating rat mast cells RBL-2H3 tightly control their major store-operated calcium influx pathway, I(CRAC...

TRPM7 is a member of the melastatin-related subfamily of TRP channels and represents a protein that contains both an ion channel and a kinase domain. The protein is ubiquitously expressed and represents the only ion channel known that is essential for cellular viability. TRPM7 is a divalent cation-selective ion channel that is permeable to Ca2+ and...

TRPM4 is a calcium-activated non-selective cation channel that is widely expressed and proposed to be involved in cell depolarization. In excitable cells, TRPM4 may regulate calcium influx by causing the depolarization that drives the activation of voltage-dependent calcium channels. We here report that insulin-secreting cells of the rat pancreatic...

This work supported by Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 236, Hermann- und Lilly-Schilling-Stiftung (R.P.), and the European Molecular Biology Organization (EMBO) (C.F.).

Receptor-mediated Ca(2+) release from the endoplasmic reticulum (ER) is often followed by Ca(2+) entry through Ca(2+)-release-activated Ca(2+) (CRAC) channels in the plasma membrane . RNAi screens have identified STIM1 as the putative ER Ca(2+) sensor and CRACM1 (Orai1; ) as the putative store-operated Ca(2+) channel. Overexpression of both protein...

Depletion of intracellular calcium stores activates store-operated calcium entry across the plasma membrane in many cells. STIM1, the putative calcium sensor in the endoplasmic reticulum, and the calcium release-activated calcium (CRAC) modulator CRACM1 (also known as Orai1) in the plasma membrane have recently been shown to be essential for contro...

Store-operated Ca2+ entry is mediated by Ca2+ release–activated Ca2+ (CRAC) channels following Ca2+ release from intracellular stores. We performed a genome-wide RNA interference (RNAi) screen in Drosophila cells to identify proteins that inhibit store-operated Ca2+ influx. A secondary patch-clamp screen identified CRACM1 and CRACM2 (CRAC modulator...

TRPM2 (previously designated TRPC7 or LTRPC2) is a Ca2+-permeable nonselective cation channel that contains a C-terminal enzymatic domain with pyrophosphatase activity, which specifically binds ADP-ribose. Cyclic ADP-ribose (cADPR) and hydrogen peroxide (H2O2) can facilitate ADPR-mediated activation of heterologously expressed TRPM2. Here, we show...

3,5-Bis(trifluoromethyl)pyrazole derivative (BTP2) or N-[4-3, 5-bis(trifluromethyl)pyrazol-1-yl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (YM-58483) is an immunosuppressive compound that potently inhibits both Ca2+ influx and interleukin-2 (IL-2) production in lymphocytes. We report here that BTP2 dosedependently enhances transient receptor potenti...

TRPM7 is a Ca2+- and Mg2+-permeable cation channel that also contains a protein kinase domain. While there is general consensus that the channel is inhibited by free intracellular Mg2+, the functional roles of intracellular levels of Mg·ATP and the kinase domain in regulating TRPM7 channel activity have been discussed controversially. To obtain ins...

The melastatin-related transient receptor potential channel TRPM2 is a plasma membrane Ca2+-permeable cation channel that is activated by intracellular adenosine diphosphoribose (ADPR) binding to the channel's enzymatic Nudix domain. Channel activity is also seen with nicotinamide dinucleotide (NAD+) and hydrogen peroxide (H2O2), but their mechanis...

Significant progress in the molecular and functional characterization of a subfamily of genes that encode melastatin-related transient receptor potential (TRPM) cation channels has been made during the past few years. This subgroup of the TRP superfamily of ion channels contains eight mammalian members and has isoforms in most eukaryotic organisms....

TRPM4 has recently been described as a calcium-activated nonselective (CAN) cation channel that mediates membrane depolarization. However, the functional importance of TRPM4 in the context of calcium (Ca2+) signaling and its effect on cellular responses are not known. Here, the molecular inhibition of endogenous TRPM4 in T cells was shown to suppre...

D-6-Deoxy-myo-inositol 1,3,4,5-tetrakisphosphate [D-6-deoxy-Ins(1,3,4,5)P(4)] 3 is a novel deoxygenated analogue of D-myo-inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P(4)] 2, a central and enigmatic molecule in the polyphosphoinositide pathway of cellular signalling. D-6-Deoxy-Ins(1,3,4,5)P(4) is a moderate inhibitor of Ins(1,4,5)P(3) 5-phospha...

Store-operated or capacitative Ca2+ entry is a prominent feature of many electrically nonexcitable cell types. It is due to Ca2+ ion permeation pathways in the plasma membrane that are activated after receptor-mediated Ca2+ release from intracellular stores. Despite hundreds of publications on the topic of store-operated Ca2+ entry and intense effo...

TRPM7 is a ubiquitously expressed and constitutively active divalent cation-selective ion channel, whose basal activity is regulated by intracellular levels of Mg(2+) and Mg.ATP. We have investigated receptor-mediated mechanisms that may actively regulate TRPM7 activity. We here report that TRPM7 currents are suppressed by intracellular GTPgammaS,...

The molecular characterization of the genes encoding the transient receptor potential (TRP) cation channels found in Drosophila photoreceptors gave rise to a systematic cloning strategy for mammalian isoforms. Using expressed sequence tag (EST) and genomic database searches, at least 20 new mammalian TRP-related genes have been cloned and the resul...

Transient receptor potential (TRP) proteins are a diverse family of proteins with structural features typical of ion channels. TRPM5, a member of the TRPM subfamily, plays an important role in taste receptors, although its activation mechanism remains controversial and its function in signal transduction is unknown. Here we characterize the functio...

TRPM7 is a polypeptide with intrinsic ion channel and protein kinase domains whose targeted deletion causes cells to experience growth arrest within 24 hr and eventually die. Here, we show that while TRPM7's kinase domain is not essential for activation of its channel, a functional coupling exists such that structural alterations of the kinase doma...

The store-operated calcium-release-activated calcium current, I (CRAC), is a major mechanism for calcium entry into non-excitable cells. I (CRAC) refills calcium stores and permits sustained calcium signalling. The relationship between inositol 1,4,5-trisphosphate receptor (InsP(3)R)-containing stores and I (CRAC) is not understood. A model of glob...

Trace metal ions such as Zn(2+), Fe(2+), Cu(2+), Mn(2+), and Co(2+) are required cofactors for many essential cellular enzymes, yet little is known about the mechanisms through which they enter into cells. We have shown previously that the widely expressed ion channel TRPM7 (LTRPC7, ChaK1, TRP-PLIK) functions as a Ca(2+)- and Mg(2+)-permeable catio...

The store-operated calcium current, ICRAC, is a major mechanism for calcium entry into non-excitable cells. ICRAC refills calcium stores and permits sustained calcium signaling. The relationship between InsP3R containing stores and ICRAC is not understood. A model of global InsP3R store depletion coupling to ICRAC activation may be simplistic, sinc...

Calcium-activated nonselective (CAN) cation channels are expressed in various excitable and nonexcitable cells supporting important cellular responses such as neuronal bursting activity, fluid secretion, and cardiac rhythmicity. We have cloned and characterized a second form of TRPM4, TRPM4b, a member of the TRP channel family, as a molecular candi...

Capacitative Ca(2+) entry (CCE) activated by release/depletion of Ca(2+) from internal stores represents a major Ca(2+) influx mechanism in lymphocytes and other nonexcitable cells. Despite the importance of CCE in antigen-mediated lymphocyte activation, molecular components constituting this mechanism remain elusive. Here we demonstrate that genet...