A5041702675- Ion channel regulation and function
- Pancreatic function and diabetes
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Cardiac electrophysiology and arrhythmias
- Calcium signaling and nucleotide metabolism
- Cellular transport and secretion
- Metabolism, Diabetes, and Cancer
- Ion Transport and Channel Regulation
- Cannabis and Cannabinoid Research
- Diabetes Treatment and Management
- Endoplasmic Reticulum Stress and Disease
- Hormonal Regulation and Hypertension
- Nicotinic Acetylcholine Receptors Study
- Mitochondrial Function and Pathology
- Diabetes and associated disorders
- Cardiomyopathy and Myosin Studies
- Adipose Tissue and Metabolism
- Lysosomal Storage Disorders Research
- Genetic Neurodegenerative Diseases
- Neuroblastoma Research and Treatments
- Apelin-related biomedical research
- Pharmacological Receptor Mechanisms and Effects
- Neuroendocrine Tumor Research Advances
- Pain Mechanisms and Treatments
University of California, Davis
2018-2025
Vanderbilt University
2014-2024
University of Utah
2024
Nashville Oncology Associates
2018
Institute of Neurobiology
2018
Vanderbilt University Medical Center
2016
Membrane contacts between endoplasmic reticulum (ER) and plasma membrane (PM), or ER-PM junctions, are ubiquitous in eukaryotic cells platforms for lipid calcium signaling homeostasis. Recent studies have revealed proteins crucial to the formation function of junctions non-neuronal cells, but little is known prominent aspiny regions mammalian brain neurons. The Kv2.1 voltage-gated potassium channel abundantly clustered at neurons first PM protein that functions organize junctions. However,...
The voltage-gated K+ channel Kv2.1 serves a major structural role in the soma and proximal dendrites of mammalian brain neurons, tethering plasma membrane (PM) to endoplasmic reticulum (ER). Although clustering at neuronal ER-PM junctions (EPJs) is tightly regulated highly conserved, its function remains unclear. By identifying evaluating proteins close spatial proximity Kv2.1-containing EPJs, we discovered that significant EPJs promote functional coupling PM L-type Ca2+ channels (LTCCs)...
β-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show inactivation β-arrestin-2 gene, barr2, in β-cells adult mice greatly impairs release glucose tolerance fed with a calorie-rich diet. Both KCl-induced secretion calcium responses were profoundly reduced (barr2) deficient β-cells. In human β-cells, barr2 knockdown abolished glucose-induced secretion. We...
Junctions between the endoplasmic reticulum (ER) and plasma membrane (PM) are specialized contacts ubiquitous in eukaryotic cells. Concentration of intracellular signaling machinery near ER-PM junctions allows these domains to serve critical roles lipid Ca2+ homeostasis. Subcellular compartmentalization protein kinase A (PKA) also regulates essential cellular functions, however, no specific association PKA junctional is known. Here, we show that brain neurons type I directed Kv2.1...
Two-pore domain K+ (K2P) channels play an important role in tuning β-cell glucose-stimulated insulin secretion (GSIS). The K2P channel TWIK-related alkaline pH-activated (TALK)-1 is linked to type 2 diabetes risk through a coding sequence polymorphism (rs1535500); however, its physiological function has remained elusive. Here, we show that TALK-1 are expressed mouse and human β-cells, where they serve as key regulators of electrical excitability GSIS. We find the rs1535500 polymorphism,...
Excessive glucocorticoid exposure has been shown to be deleterious for pancreatic β-cell function and insulin release. However, glucocorticoids at physiological levels are essential many homeostatic processes, including glycemic control. We show that corticosterone cortisol their less active precursors 11-dehydrocorticosterone (11-DHC) cortisone suppress voltage-dependent Ca2+ channel fluxes in rodent as well human β-cells. secretion, maximal ATP/ADP responses glucose, identity were all...
Significance In hippocampal neurons, gene expression is triggered by electrical activity and Ca 2+ entry via L-type Cav1.2 channels in a process called excitation–transcription coupling. We identified domain on the voltage-gated K + channel Kv2.1 that promotes clustering of at endoplasmic reticulum–plasma membrane junctions soma neurons. Importantly, we discovered disrupting this Kv2.1-mediated somatic microdomain critical for depolarization-induced
Calcium entry through voltage-dependent Ca(2+) channels (VDCCs) is required for pancreatic β-cell insulin secretion. The 2-pore-domain acid-sensitive potassium channel (TASK-1) regulates neuronal excitability and VDCC activation by hyperpolarizing the plasma membrane potential (Δψp); however, a role TASK-1 unknown. Here we examined influence of activity on Δψp secretion during secretagogue stimulation. were found to be highly expressed in human rodent islets localized β-cells. TASK-1-like...
Abstract Lysosomes communicate through cholesterol transfer at endoplasmic reticulum (ER) contact sites. At these sites, the Niemann Pick C1 transporter (NPC1) facilitates removal of from lysosomes, which is then transferred to ER for distribution other cell membranes. Mutations in NPC1 result buildup within leading Niemann-Pick Type C (NPC) disease, a progressive and fatal neurodegenerative disorder. The molecular mechanisms connecting loss NPC-associated neuropathology remain unknown. Here...
Voltage-gated K + channels of the Kv2 family are highly expressed in brain and play dual roles regulating neuronal excitability organizing endoplasmic reticulum - plasma membrane (ER-PM) junctions. Studies heterologous cells suggest that Kv2.1 Kv2.2 co-assemble with “electrically silent” KvS subunits to form heterotetrameric distinct biophysical properties, but prevalence localization these native neurons is unknown. Here, using mass spectrometry-based proteomics, we identified five as...
Glucose regulation of pancreatic α-cell Ca(2+) entry through voltage-dependent channels is essential for normal glucagon secretion and becomes defective during the pathogenesis diabetes mellitus. The 2-pore domain K(+) channel, TWIK-related acid-sensitive channel 1 (TASK-1), an important modulator membrane voltage entry. However, its role in α-cells has not been determined. Therefore, we addressed how TASK-1 regulate electrical activity, entry, secretion. We find that expressed human rodent...
The two-pore-domain potassium (K2P) channel TREK-2 serves to modulate plasma membrane potential in dorsal root ganglia c-fiber nociceptors, which tunes electrical excitability and nociception. Thus, channels are considered a therapeutic target for treating pain; however, there currently no selective pharmacological tools channels. Here we report the identification of first activators using high-throughput fluorescence-based thallium (Tl+) flux screen (HTS). An initial pilot with bioactive...
An ER-localized K + channel could be targeted to suppress ER stress in diabetic pancreatic β cells.
Developmental and epileptic encephalopathies (DEE) are a group of severe epilepsies that usually present with intractable seizures, developmental delay, often have elevated risk for premature mortality. Numerous genes been identified as monogenic cause DEE, including KCNB1. The voltage-gated potassium channel KV2.1, encoded by KCNB1, is primarily responsible delayed rectifier currents important regulators excitability in electrically excitable cells, neurons. In addition to its canonical...
Single-cell RNA sequencing studies have revealed that the type-2 diabetes associated two-pore domain K+ (K2P) channel TALK-1 is abundantly expressed in somatostatin-secreting δ-cells. However, a physiological role for δ-cells remains unknown. We previously determined β-cells, flux through endoplasmic reticulum (ER)-localized channels enhances ER Ca2+ leak, modulating handling and insulin secretion. As glucose amplification of islet somatostatin release relies on Ca2+-induced (CICR) from...
In arterial myocytes, the canonical function of voltage-gated Ca
Glucose-stimulated insulin secretion (GSIS) relies on β-cell Ca2+ influx, which is modulated by the two-pore-domain K+ (K2P) channel, TALK-1. A gain-of-function polymorphism in KCNK16, gene encoding TALK-1, increases risk for developing type-2 diabetes. While TALK-1 serves an important role modulating GSIS, regulatory mechanism(s) that control channels are unknown. Therefore, we employed a membrane-specific yeast two-hybrid (MYTH) assay to identify TALK-1-interacting proteins human islets,...
Pancreatic α-cells exhibit oscillations in cytosolic Ca 2+ (Ca c ), which control pulsatile glucagon (GCG) secretion. However, the mechanisms that modulate α-cell have not been elucidated. As β-cell are regulated part by -activated K + (K slow ) currents, this work investigated role of handling and GCG α-Cells displayed currents were dependent on influx through L- P/Q-type voltage-dependent channels (VDCCs) as well released from endoplasmic reticulum stores. α-Cell was decreased...
Mitochondrial Ca2+ ([Ca2+]m) homeostasis is critical for β-cell function and becomes disrupted during the pathogenesis of diabetes. [Ca2+]m uptake dependent on elevations in cytoplasmic ([Ca2+]c) endoplasmic reticulum ([Ca2+]ER) release, both which are regulated by two-pore domain K+ channel TALK-1. Here, utilizing a novel TALK-1-knockout (β-TALK-1-KO) mouse model, we found that TALK-1 limited accumulation ATP production. However, following exposure to high-fat diet (HFD), ATP-linked...
Abstract Voltage-gated K + channels of the Kv2 family are highly expressed in brain and play dual roles regulating neuronal excitability organizing endoplasmic reticulum - plasma membrane (ER- PM) junctions. Studies heterologous cells suggest that two pore-forming alpha subunits Kv2.1 Kv2.2 assemble with “electrically silent” KvS to form heterotetrameric distinct biophysical properties. Here, using mass spectrometry-based proteomics, we identified five as components native immunopurified...
Abstract Neuronal information processing depends on converting membrane depolarizations into compartmentalized biochemical signals that can modify neuronal activity and structure. However, our understanding of how neurons translate electrical specific responses remains limited, especially in the soma where gene expression ion channel function are crucial for activity. Here, I emphasize importance physically compartmentalizing action potential‐triggered reactions within soma. Emerging...
Abstract In arterial myocytes, the canonical function of voltage-gated Ca V 1.2 and K 2.1 channels is to induce myocyte contraction relaxation through their responses membrane depolarization, respectively. Paradoxically, also plays a sex-specific role by promoting clustering activity channels. However, impact protein organization on remains poorly understood. We discovered that forms micro-clusters, which can transform into large macro-clusters when critical site (S590) in channel...