Alexander Stokes

University of Hawaiʻi at Mānoa | UH Manoa · Department of Cell and Molecular Biology

TRPV1 (transient receptor potential cation channel, subfamily V, member 1) is best studied in peripheral sensory neurons as a pain receptor; however TRPV1 is expressed in numerous tissues and cell types including those of the cardiovascular system. TRPV1 expression is upregulated in the hypertrophic heart, and the channel is positioned to receive s...

Heart failure is becoming a global epidemic. It exerts a staggering toll on quality of life, and substantial medical and economic impact. In a pre-clinical model of cardiac hypertrophy and heart failure, we were able to overcome loss of heart function by administering the TRPV1 antagonist BCTC (4-(3-Chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)pheny...

As exceptionally calcium selective and store-operated channels, Orai channels play a prominent role in cellular calcium signaling. While most studied in the immune system, we are beginning to recognize that Orai1 provides unique calcium signaling pathways in numerous tissue contexts. To assess the involvement of Orai1 in cardiac hypertrophy we used...

Abstract Two pore channels (TPC1, 2, and 3) are recently identified endolysosmal ion channels, but remain poorly characterized. In this study, we show for the first time a role for TPC1 in cytokinesis, the final step in cell division. HEK 293 T-REx cells inducibly overexpressing TPC1 demonstrated a lack of proliferation accompanied by multinucleati...

Background Activation of the atrial natriuretic signaling pathway is intrinsic to the pathological responses associated with a range of cardiovascular diseases that stress the heart, especially those involved in sustained cardiac pressure overload which induces hypertrophy and the pathological remodeling that frequently leads to heart failure. We i...

Ethnopharmacological relevance Traditional pharmacopeias have been developed by multiple cultures and evaluated for efficacy and safety through both historical/empirical iteration and more recently through controlled studies using Western scientific paradigms and an increasing emphasis on data science methodologies for network pharmacology. Traditi...

Hypoxia sensors are essential for regulating local oxygen (O2) homeostasis within the body. This is especially pertinent within the CNS, which is particularly vulnerable to O2 deprivation due to high energetic demand. Here, we reveal hypoxia-monitoring function exerted by astrocytes through an O2-regulated protein trafficking mechanism within the C...

Calcium entry is central to the functional processes in mast cells and basophils that contribute to the induction and maintenance of inflammatory responses. Mast cells and basophils express an array of calcium channels, which mediate responses to diverse stimuli triggered by small bioactive molecules, physicochemical stimuli and immunological input...

Nociceptive Transient Receptor Potential channels such as TRPV1 are targets for treating pain. Both antagonism and agonism of TRP channels can promote analgesia, through inactivation and chronic desensitization. Since plant-derived mixtures of cannabinoids and the Cannabis component myrcene have been suggested as pain therapeutics, we screened terp...

Cannabinoid compounds are potential analgesics. Users of medicinal Cannabis report efficacy for pain control, clinical studies show that cannabis can be effective and opioid sparing in chronic pain, and some constituent cannabinoids have been shown to target nociceptive ion channels. Here, we explore and compare a suite of cannabinoids for their im...

Introduction: Medical cannabis patients receive clinical benefits from the secondary metabolites of the plant, which contain a variety of cannabinoids and terpenoids in combinations that can be used to classify the chemovars. State-regulated medical cannabis programs rely on breeder-reported "strain" names both within diversion control systems and...

Large membrane derangements in the form of non-detaching blebs or membrane protrusions occur in a variety of cell stress and physiological situations and do not always reflect apoptotic processes. They have been studied in model mast cells under conditions of cell stress, but their potential physiological relevance to mast cell function and formati...

Mast cell lipid bodies are key to initiation, maintenance and resolution of inflammatory responses in tissue. Mast cell lines, primary bone marrow-derived mast cells and peripheral blood basophils present a ‘steatotic’ phenotype in response to chronic insulin exposure, where cells become loaded with lipid bodies. Here we show this state is associat...

Parkinson’s disease (PD) involves neuroinflammation, excitotoxicity, mitochondrial dysfunction, and diminished trophic support. The endo-cannabinoid system (comprising small bioactive compounds, their synthetic and catabolic enzymes, their metabotropic and ionotropic receptors, and their transporters) has been implicated in neurophysiology and neur...

Objective Secretory granules (SG) and lipid bodies (LB) are the primary organelles that mediate functional responses in mast cells. SG contains histamine and matrix-active proteases, while LB are reservoirs of arachidonic acid and its metabolites, precursors for rapid synthesis of eicosanoids such as LTC4. Both of these compartments can be dynamica...

Zika virus (ZIKV) is an emerging mosquito-borne pathogen. ZIKV infection is linked to the development of severe fetal abnormalities that include spontaneous abortion, stillbirth, hydranencephaly, and microcephaly. ZIKV outbreaks have been recorded in the United States. We recently demonstrated the first congenital ZIKV infection in the United State...

STROBE Checklist. (DOC)

Entomological protocols for aging blowfly (Diptera: Calliphoridae) larvae to estimate the time of colonization (TOC) are commonly used to assist in death investigations. While the methodologies for analyzing fly larvae differ, most rely on light microscopy, genetic analysis, or, more rarely, electron microscopy. This pilot study sought to improve r...

Major components of the human ion trafficking system identified in the coral genomic data.DOI: http://dx.doi.org/10.7554/eLife.13288.006

Taxonomic compilation and presence/absence in each taxon for genes involved in oxidative stress, DNA repair, cell cycle and apoptosis. The values in parentheses show the number of taxa in which the gene sequence was recovered in the genomic database. DOI: http://dx.doi.org/10.7554/eLife.13288.022

Coral genomic data compiled in this study and their attributes.DOI: http://dx.doi.org/10.7554/eLife.13288.004

Transcriptome and genome data from twenty stony coral species and a selection of reference bilaterians were studied to elucidate coral evolutionary history. We identified genes that encode the proteins responsible for the precipitation and aggregation of the aragonite skeleton on which the organisms live, and revealed a network of environmental sen...

Berry, Marla J

Kava is a soporific, anxiolytic and relaxant in widespread ritual and recreational use throughout the Pacific. Traditional uses of kava by indigenous Pacific Island peoples reflect a complex pharmacopeia, centered on GABA-ergic effects of the well-characterized kavalactones. However, peripheral effects of kava suggest active components other than t...

There is well-established variability in the numbers of lipid bodies (LB) in macrophages, eosinophils, and neutrophils. Similarly to the steatosis observed in adipocytes and hepatocytes during hyperinsulinemia and nutrient overload, immune cell LB hyper-accumulate in response to bacterial and parasitic infection and inflammatory presentations. Rece...

Carbon nanotubes (CNT) are environmental challenges to the respiratory and gastrointestinal mucosa, and to the dermal immune system. Mast cells (MC) are pro-inflammatory immunocytes that reside at these interfaces with the environment. Mast cells are sources of pro-inflammatory mediators (histamine, serotonin, matrix-active proteases, eicosanoids,...

Loss of plasma membrane asymmetry is a hallmark of apoptosis, but lipid bilayer asymmetry and loss of asymmetry can contribute to numerous cellular functions and responses that are independent of programmed cell death. Exofacial exposure of phosphatidylserine occurs in lymphocytes and mast cells after antigenic stimulation and in the absence of apo...

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by increased sensitivity to infection by the β-subtype of human papillomaviruses (β-HPVs), causing persistent, tinea versicolor-like dermal lesions. In a majority of affected individuals, these macular lesions progress to invasive cutaneous squamous cell carcinoma (CSCC) in...

Kava ('Awa) is a traditional water-based beverage in Pacific island communities, prepared from the ground root and stems of Piper methysticum. Kava use is associated with an ichthyotic dermatitis and delayed type hypersensitivity reactions. In the current study we collated preparative methodologies from cultural practitioners and recreational kava...

C57BL/6-KitW-sh/W-sh mice are generally regarded as a mast cell-deficient model, as they lack the necessary kit receptor for mast cell development. Further characterization of this strain, however, indicates that C57BL/6-KitW-sh/W-sh mice also have a disruption in the Corin gene. Corin is a transmembrane serine protease critical for processing atri...

Methods are provided of treating cardiac hypertrophy and heart failure in a mammalian subject comprising administering to the subject an anti-hypertrophic effective amount of an ion channel TRPV1 inhibitor. The methods include treatment of a symptom of cardiac hypertrophy in the subject comprises cardiac remodeling, cardiac fibrosis, apoptosis, hyp...

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Mast cells are granular immunocytes that reside in the body's barrier tissues. These cells orchestrate inflammatory responses. Proinflammatory mediators are stored in granular structures within the mast cell cytosol. Control of mast cell granule exocytosis is a major therapeutic goal for allergic and inflammatory diseases. However, the proteins tha...

Mast cells are tissue-resident immune effector cells. They respond to diverse stimuli by releasing potent biological mediators into the surrounding tissue, and initiating inflammatory responses that promote wound healing and infection clearance. In addition to stimulation via immunological routes, mast cells also respond to polybasic secretagogues...

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...

Certain TRP cation channels confer the ability to sense environmental stimuli (heat, cold, pressure, osmolarity) across physiological and pathophysiological ranges. TRPA1 is a TRP-related channel that responds to cold temperatures, and pungent compounds that include the cold-mimetic icilin and cannabinoids. The initial report of TRPA1 as a transfor...

The inositol (1,4,5) trisphosphate 3-kinase (ITP3K) phosphorylates Ins (1,4,5) P3 to produce Ins (1,3,4,5) P4. The ITP3K substrate, InsP3, and its product, InsP4, both have the potential to regulate mast cell function. Here, we explore the effects of dominant inhibition of ITP3K upon secretory responses and Ras GTPase activation following antigenic...

The transient receptor potential, sub-family Vanilloid (TRPV)(2) cation channel is activated in response to extreme temperature elevations in sensory neurons. However, TRPV2 is widely expressed in tissues with no sensory function, including cells of the immune system. Regulation of GRC, the murine homolog of TRPV2 has been studied in insulinoma cel...

Cutaneous mast cell responses to physical (thermal, mechanical, or osmotic) stimuli underlie the pathology of physical urticarias. In vitro experiments suggest that mast cells respond directly to these stimuli, implying that a signaling mechanism couples functional responses to physical inputs in mast cells. We asked whether transient receptor pote...

TRPV ion channels transduce a range of temperature stimuli. We proposed that analysis of the protein-protein interactions made by TRPV2 might give insight into the key issues surrounding this channel. These issues include the potential functional significance of TRPV2 in non-sensory tissues, the molecules involved in transducing its activation sign...

A high prevalence rate of obsessive-compulsive disorder (OCD) among Hawaiian adolescents, particularly Native Hawaiians, has been reported. Because Native Hawaiian and other Polynesian youth are at an increased risk for rheumatic fever, caused by an autoimmune response to group A beta-hemolytic streptococci, we hypothesized that the genetic and env...

Cannabinoid modulation of immune responses is a pathological consequence of marijuana abuse and a potential outcome of therapeutic application of the drug. Moreover, endogenous cannabinoids are physiological immune regulators. In the present report, we describe alterations in gene transcription that occur after cannabinoid exposure in a mast cell l...

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...

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...

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The molecular mechanisms that regulate basal or background entry of divalent cations into mammalian cells are poorly understood. Here we describe the cloning and functional characterization of a Ca2+- and Mg2+-permeable divalent cation channel, LTRPC7 (nomenclature compatible with that proposed in ref. 1), a new member of the LTRPC family of putati...

Free ADP-ribose (ADPR), a product of NAD hydrolysis and a breakdown product of the calcium-release second messenger cyclic ADPR (cADPR), has no defined role as an intracellular signalling molecule in vertebrate systems. Here we show that a 350-amino-acid protein (designated NUDT9) and a homologous domain (NUDT9 homology domain) near the carboxy ter...

Given the importance of phosphotyrosine signaling in growth cone dynamics, we have examined the embryonic and adult expression of receptor-like protein tyrosine phosphatases in sensory neurons and studied their responsiveness to nerve lesions in young adult animals. The phosphatases LAR, PTPsigma, and PTPalpha are expressed in most neurons of E14 a...