A5083775247- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Neuroscience and Neuropharmacology Research
- Neuroscience and Neural Engineering
- Ion Channels and Receptors
- Receptor Mechanisms and Signaling
- Cardiomyopathy and Myosin Studies
- Nitric Oxide and Endothelin Effects
- Signaling Pathways in Disease
- Mitochondrial Function and Pathology
- Ion Transport and Channel Regulation
- Nicotinic Acetylcholine Receptors Study
- stochastic dynamics and bifurcation
- Hormonal Regulation and Hypertension
- Cardiovascular Function and Risk Factors
- Renin-Angiotensin System Studies
- Neural dynamics and brain function
- Heart Failure Treatment and Management
- Microtubule and mitosis dynamics
- Heart Rate Variability and Autonomic Control
- Connexins and lens biology
- Cellular transport and secretion
- Cardiac, Anesthesia and Surgical Outcomes
- Genetic Neurodegenerative Diseases
- Pluripotent Stem Cells Research
University of California, Davis
2016-2025
Universidade Estadual Paulista (Unesp)
2025
Hospital Universitario de Gran Canaria Doctor Negrín
2018-2024
University of California, Los Angeles
2023
American Jewish University
2023
Precision for Medicine (United States)
2023
University of California, San Diego
2023
University of Washington
2007-2017
Howard Hughes Medical Institute
2010-2017
Montreal Neurological Institute and Hospital
2017
Local increases in intracellular calcium ion concentration ([Ca 2+ ] i ) resulting from activation of the ryanodine-sensitive calcium-release channel sarcoplasmic reticulum (SR) smooth muscle cause arterial dilation. Ryanodine-sensitive, spontaneous local [Ca (Ca sparks) SR were observed just under surface membrane single cells myogenic cerebral arteries. Ryanodine and thapsigargin inhibited Ca sparks -dependent potassium (K currents, suggesting that activate K channels. Furthermore,...
Cardiac hypertrophy and heart failure caused by high blood pressure were studied in single myocytes taken from hypertensive rats (Dahl SS/Jr) SH-HF failure. Confocal microscopy patch-clamp methods used to examine excitation-contraction (EC) coupling, the relation between plasma membrane calcium current ( I Ca ) evoked release sarcoplasmic reticulum (SR), which was visualized as “calcium sparks.” The ability of trigger SR both hypertrophied failing hearts reduced. Because density...
Mitochondrial dysfunction has been implicated in several cardiovascular diseases; however, the roles of mitochondrial oxidative stress and DNA damage hypertensive cardiomyopathy are not well understood.We evaluated contribution reactive oxygen species (ROS) to cardiac hypertrophy failure by using genetic mouse models overexpressing catalase targeted mitochondria peroxisomes.Angiotensin II increases ROS cardiomyocytes, concomitant with increased protein carbonyls, deletions, autophagy...
Background— Age is a major risk for cardiovascular diseases. Although mitochondrial reactive oxygen species have been proposed as one of the causes aging, their role in cardiac aging remains unclear. We previously shown that overexpression catalase targeted to mitochondria (mCAT) prolongs murine median lifespan by 17% 21%. Methods and Results— used echocardiography study function cohorts wild-type mCAT mice. Changes found mice recapitulate human aging: age-dependent increases left...
Sensitization of the pain-transducing ion channel TRPV1 underlies thermal hyperalgesia by proalgesic agents such as nerve growth factor (NGF). The currently accepted model is that NGF-mediated increase in function during utilizes activation phospholipase C (PLC) to cleave PIP2, proposed tonically inhibit TRPV1. In this study, we tested PLC and found two lines evidence directly challenge its validity: (1) polylysine, a cationic phosphoinositide sequestering agent, inhibited instead...
Hypertension is a clinical syndrome characterized by increased vascular tone. However, the molecular mechanisms underlying dysfunction during acquired hypertension remain unresolved. Localized intracellular Ca2+ release events through ryanodine receptors (Ca2+ sparks) in sarcoplasmic reticulum are tightly coupled to activation of large-conductance, Ca2+-activated K+ (BK) channels provide hyperpolarizing influence that opposes vasoconstriction. In this study we tested hypothesis reduction...
Abstract Ca 2+ sparks, the elementary events underlying excitation-contraction (E-C) coupling, occur when sarcoplasmic reticulum (SR) release channels open. They are activated locally by influx through sarcolemmal (SL) channels. By measuring probability of spark occurrence under conditions in which their is low, we address two important questions raised our recent work: (1) When a triggered, how many SL (at minimum) contribute to its activation? (2) What relation between subcellular local...
Hypertension is a clinical syndrome characterized by increased vascular tone. However, the molecular mechanisms underlying dysfunction during acquired hypertension remain unresolved. Localized intracellular Ca2+ release events through ryanodine receptors (Ca2+ sparks) in sarcoplasmic reticulum are tightly coupled to activation of large-conductance, Ca2+-activated K+ (BK) channels provide hyperpolarizing influence that opposes vasoconstriction. In this study we tested hypothesis reduction...
Ca 2+ influx through L-type channels (LTCCs) influences numerous physiological processes ranging from contraction in muscle and memory neurons to gene expression many cell types. However, the spatiotemporal organization of functional LTCCs has been nearly impossible investigate because methodological limitations. Here, we examined LTCC function with high temporal spatial resolution using evanescent field fluorescence microscopy. Surprisingly, found that operated functionally organized...
The molecular mechanisms underlying increased arterial tone during hypertension are unclear. In vascular smooth muscle, localized Ca 2+ release events through ryanodine-sensitive channels located in the sarcoplasmic reticulum (Ca sparks) activate large-conductance, -sensitive K + (BK) channels. sparks and BK provide a negative feedback mechanism that hyperpolarizes muscle thereby opposes vasoconstriction. this study, we examined channel function Wistar-Kyoto (WKY) rats with borderline...
Sympathetic stimulation of the heart increases force contraction and rate ventricular relaxation by triggering protein kinase (PK)A-dependent phosphorylation proteins that regulate intracellular calcium. We hypothesized scaffolding cAMP signaling complexes AKAP5 is required for efficient sympathetic calcium transients.We examined function in β-adrenergic cascade.We used imaging electrophysiology to examine response cardiomyocytes isolated from wild type mutant animals. The regulation...
Local Ca 2+ signaling at specialized regions of endothelial cell–smooth muscle contact is impaired in hypertension.
Rationale : L-Type (Cav1.2) Ca 2+ channels are critical regulators of muscle and neural function. Although Cav1.2 channel activity varies regionally, little is known about the mechanisms underlying this heterogeneity. Objective To test hypothesis that can gate coordinately. Methods Results We used optical electrophysiological approaches to record in cardiac, smooth muscle, tsA-201 cells expressing channels. Consistent with our hypothesis, we found small clusters open close tandem....
A-kinase anchoring proteins (AKAPs) tether the cAMP-dependent protein kinase (PKA) to intracellular sites where they preferentially phosphorylate target substrates. Most AKAPs exhibit nanomolar affinity for regulatory (RII) subunit of type II PKA holoenzyme, whereas dual-specificity also bind I (RI) with 10–100-fold lower affinity. A range cellular, biochemical, biophysical, and genetic approaches comprehensively establish that sphingosine interacting (SKIP) is a truly I-specific AKAP....
Background— Cardiac dysfunction in failing hearts of human patients and animal models is associated with both microtubule densification transverse-tubule (T-tubule) remodeling. Our objective was to investigate whether contributes T-tubule remodeling excitation–contraction coupling heart disease. Methods Results— In a mouse model pressure overload–induced cardiomyopathy by transaortic banding, colchicine, depolymerizer, significantly ameliorated cardiac dysfunction. cultured cardiomyocytes,...
The ability to extract somatic cells from a patient and reprogram them pluripotency opens up new possibilities for personalized medicine. Induced pluripotent stem (iPSCs) have been employed generate beating cardiomyocytes patient's skin or blood cells. Here, iPSC methods were used starting the urine of with Duchenne muscular dystrophy (DMD). Urine was chosen as material because it contains adult called urine-derived (USCs). USCs express canonical reprogramming factors c-myc klf4, possess...
Ca 2+ influx via L-type v 1.2 channels is essential for multiple physiological processes, including gene expression, excitability, and contraction. Amplification of the signals produced by opening these a hallmark many intracellular signaling cascades, excitation-contraction coupling in heart. Using optogenetic approaches, we discovered that form clusters varied sizes ventricular myocytes. Physical interaction between their C-tails renders them capable coordinating gating, thereby amplifying...
In the heart, reliable activation of Ca2+ release from sarcoplasmic reticulum during plateau ventricular action potential requires synchronous opening multiple CaV1.2 channels. Yet mechanisms that coordinate this simultaneous every heartbeat are unclear. Here, we demonstrate channels form clusters undergo dynamic, reciprocal, allosteric interactions. This ‘functional coupling’ facilitates influx by increasing adjoined and occurs through C-terminal-to-C-terminal These interactions initiated...
Transient receptor potential vanilloid 4 (TRPV4) channels are Ca2+-permeable, nonselective cation expressed in multiple tissues, including smooth muscle. Although TRPV4 play a key role regulating vascular tone, the mechanisms controlling Ca2+ influx through these arterial myocytes poorly understood. Here, we tested hypothesis that anchoring protein AKAP150 and kinase C (PKC) critical regulation of during angiotensin II (AngII) signaling. Super-resolution imaging revealed gathered into puncta...
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)...
The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential energy source for normal function of muscle during each beat, as it powers ion transport, intracellular Ca 2+ handling, and actin–myosin cross-bridge cycling. Despite this, the impact excitation–contraction coupling ATP concentration ([ATP] i ) myocytes poorly understood. Here, we conducted real-time measurements [ATP]...