A5037511735- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Ion Transport and Channel Regulation
- Neuroscience and Neuropharmacology Research
- Ion Channels and Receptors
- Mosquito-borne diseases and control
- Insect Resistance and Genetics
- Genetics, Aging, and Longevity in Model Organisms
- Insect and Pesticide Research
- Cardiac Ischemia and Reperfusion
- Neuroendocrine regulation and behavior
- Insect Pest Control Strategies
- Pancreatic function and diabetes
- Neurobiology and Insect Physiology Research
- Neuroscience and Neural Engineering
- Cardiac Arrest and Resuscitation
- Nicotinic Acetylcholine Receptors Study
- Phosphodiesterase function and regulation
- Coordination Chemistry and Organometallics
- Electrolyte and hormonal disorders
- Connexins and lens biology
- Nanopore and Nanochannel Transport Studies
- bioluminescence and chemiluminescence research
- Cholinesterase and Neurodegenerative Diseases
- Lipid Membrane Structure and Behavior
Vanderbilt University Medical Center
2016-2025
Vanderbilt University
2016-2025
Center for Discovery
2025
University of South Florida
2022
Medical College of Wisconsin
2022
Nashville Oncology Associates
2015-2021
Vanderbilt Health
2013-2020
Universitat Jaume I
2019
University of Nebraska Medical Center
2018
Icahn School of Medicine at Mount Sinai
2018
Polarization of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, to apical plasma membrane epithelial cells is critical for vectorial transport in variety epithelia, including airway, pancreas, intestine, and kidney. However, motifs that localize CFTR are unknown. We report last 3 amino acids COOH-terminus (T-R-L) comprise PDZ-interacting domain required polarization human airway kidney cells. In addition, mutant, S1455X, which lacks 26...
The G-protein activated, inward-rectifying potassium (K+) channels, "GIRKs", are a family of ion channels (Kir3.1-Kir3.4) that has been the focus intense research interest for nearly two decades. GIRKs comprised various homo- and heterotetrameric combinations four different subunits. These subunits expressed in variety regions throughout central nervous system periphery. body GIRK implicates processes as diverse controlling heart rhythm, to effects on reward/addiction, modulation response...
To fertilize an oocyte, the membrane potential of both mouse and human sperm must hyperpolarize (become more negative inside). Determining molecular mechanisms underlying this hyperpolarization is vital for developing new contraceptive methods detecting causes idiopathic male infertility. In sperm, caused by activation sperm-specific potassium (K+) channel SLO3 [C. M. Santi et al., FEBS Lett.584, 1041-1046 (2010)]. it has long been unclear whether depends on or ubiquitous K+ SLO1 [N....
Herein we describe our initial work on the K2P family of potassium ion channels with chemical optimization and characterization a novel series TWIK-Related K+ Channel (TREK)-1/2 dual activators TREK-2 preferring derived from high-throughput screening hit. The exercise provided TREK good CNS penetration others low exposure to enable exploration both central peripheral activation. From this, ONO-2920632 (VU6011887 = 19b) emerged as reasonably potent (human Tl+; TREK-1 EC50 2.8 μM (95% Emax),...
Polarization of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel to the apical plasma membrane in epithelial cells is critical for vectorial transport. Previously, we reported that C terminus CFTR constitutes PDZ-interacting domain required polarization and interaction with PDZ domain-containing protein EBP50 (NHERF). domains are typically composed C-terminal three five amino acids, which QDTRL. Our goal was identify key acid(s) regard its...
Abstract Insecticide resistance is a growing threat to mosquito control programs around the world, thus creating need discover novel target sites and target-specific compounds for insecticide development. Emerging evidence suggests that inward rectifier potassium (Kir) channels represent viable molecular targets developing insecticides with new mechanisms of action. Here we describe discovery characterization VU041, submicromolar-affinity inhibitor Anopheles (An.) gambiae Aedes (Ae. )...
The renal outer medullary potassium channel (ROMK) is expressed in the kidney tubule and critically regulates sodium balance. physiological functions of other inward rectifying K<sup>+</sup> (Kir) channels nephron, such as Kir7.1, are less well understood part due to lack selective pharmacological probes targeting rectifiers. In an effort identify Kir probes, we performed a fluorescence-based, high-throughput screen (HTS) 126,009 small molecules for modulators ROMK function. Several...
The renal outer medullary potassium (K<sup>+</sup>) channel, ROMK (Kir1.1), is a putative drug target for novel class of loop diuretic that would lower blood volume and pressure without causing hypokalemia. However, the lack selective inhibitors has hindered efforts to assess its therapeutic potential. In high-throughput screen small-molecule modulators ROMK, we previously identified potent moderately antagonist, 7,13-bis(4-nitrobenzyl)-1,4,10-trioxa-7,13-diazacyclopentadecane (VU590), also...
Mosquito-borne diseases such as malaria and dengue fever take a large toll on global health. The primary chemical agents used for controlling mosquitoes are insecticides that target the nervous system. However, emergence of resistance in mosquito populations is reducing efficacy available insecticides. development new therefore urgent. Here we show VU573, small-molecule inhibitor mammalian inward-rectifying potassium (Kir) channels, inhibits Kir channel cloned from renal (Malpighian) tubules...
ATP-sensitive potassium (KATP) channels play a key role in mediating glucose-stimulated insulin secretion by coupling metabolic signals to β-cell membrane potential. Loss of KATP channel function due mutations ABCC8 or KCNJ11, genes encoding the sulfonylurea receptor 1 (SUR1) inwardly rectifying Kir6.2, respectively, results congenital hyperinsulinism. Many SUR1 prevent trafficking proteins from endoplasmic reticulum cell surface. Channel inhibitors, including sulfonylureas and...
The inward rectifier potassium (Kir) channel Kir4.1 (<i>KCNJ10</i>) carries out important physiologic roles in epithelial cells of the kidney, astrocytes central nervous system, and stria vascularis inner ear. Loss-of-function mutations <i>KCNJ10</i> lead to EAST/SeSAME syndrome, which is characterized by epilepsy, ataxia, renal salt wasting, sensorineural deafness. Although genetic approaches have been indispensable for establishing importance normal function these tissues, availability...
Malignant migrating partial seizures of infancy is a rare, devastating form epilepsy most commonly associated with gain-of-function mutations in the potassium channel, Slack. Not only this condition almost completely pharmacoresistant, there are not even selective drug-like tools available to evaluate whether inhibition these overactivated, mutant Slack channels may represent viable path forward toward new antiepileptic therapies. Therefore, we used high-throughput thallium flux assay screen...
Volume-regulated anion channels (VRACs) mediate volume regulatory Cl- and organic solute efflux from vertebrate cells. VRACs are heteromeric assemblies of LRRC8A-E proteins with unknown stoichiometries. Homomeric LRRC8A LRRC8D have a small pore, hexameric structure. However, these either non-functional or exhibit abnormal regulation pharmacology, limiting their utility for structure-function analyses. We circumvented limitations by developing novel homomeric LRRC8 chimeric functional...
Summary Variations in the KCNJ6 gene appear to influence both acute and chronic pain phenotypes. G-protein coupled inwardly rectifying potassium (GIRK) channels are effectors determining degree of analgesia experienced upon opioid receptor activation by endogenous exogenous opioids. The impact GIRK-related genetic variation on human responses has received little research attention. We used a tag single nucleotide polymorphism (SNP) approach comprehensively examine pain-related effects KCNJ3...
Vector-borne diseases such as dengue fever and malaria, which are transmitted by infected female mosquitoes, affect nearly half of the world's population. The emergence insecticide-resistant mosquito populations is reducing effectiveness conventional insecticides threatening current vector control strategies, has created an urgent need to identify new molecular targets against novel classes can be developed. We previously demonstrated that small molecule inhibitors mammalian Kir channels...
Protons regulate electrogenic sodium absorption in a variety of epithelia, including the cortical collecting duct, frog skin, and urinary bladder. Recently, three subunits (α, β, γ) coding for epithelial channel (ENaC) were cloned. However, it is not known whether pH regulates Na + channels directly by interacting with one ENaC or indirectly regulatory protein. As first step to identifying molecular mechanisms proton-mediated regulation apical membrane permeability we examined effect on...
CLH-3b is a Caenorhabditis elegans ClC anion channel that expressed in the worm oocyte. The activated during oocyte meiotic maturation and response to cell swelling by serine/threonine dephosphorylation events mediated type 1 phosphatases GLC-7α GLC-7β. We have now identified new member of Ste20 kinase superfamily, GCK-3, interacts with COOH terminus via specific binding motif. GCK-3 inhibits phosphorylation-dependent manner when two proteins are coexpressed HEK293 cells. clh-3 gck-3...