Bertil Hille

Bertil Hille
University of Washington Seattle | UW · Department of Physiology and Biophysics

About

259
Publications
24,252
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45,253
Citations
Additional affiliations
September 1968 - present
University of Washington Seattle
Position
  • Professor (Full)

Publications

Publications (259)
Article
Full-text available
Phosphoinositide membrane lipids are ubiquitous low-abundance signaling molecules. They direct many physiological processes that involve ion channels, membrane identification, fusion of membrane vesicles, and vesicular endocytosis. Pools of these lipids are continually broken down and refilled in living cells, and the rates of some of these reactio...
Article
Biophysics is a way of approaching biological problems through numbers, physical laws, models, and quantitative logic. In a long scientific career, I have seen the formation and fruition of the ion channel concept through biophysical study. Marvelous discoveries were made as our instruments evolved from vacuum tubes to transistors; computers evolve...
Article
This retrospective traces the hypothesis of ion channels from an early statement in a 1970 essay in this journal (Hille, B., 1970, Prog. Biophys. Mol. Biol. 21, 1–32) to its realization today in biophysical, molecular, biochemical, and structural terms. The Na⁺ and K⁺ channels of the action potential have been isolated, reconstituted, cloned, mutat...
Article
The pineal gland secretes melatonin principally at night. Regulated by norepinephrine released from sympathetic nerve terminals, adrenergic receptors on pinealocytes activate aralkylamine N -acetyltransferase that converts 5-hydroxytryptamine (5-HT, serotonin) to N -acetylserotonin, the precursor of melatonin. Previous studies from our group and ot...
Article
β-arrestins regulate many cellular functions including intracellular signaling and desensitization of G protein–coupled receptors (GPCRs). Previous studies show that β-arrestin signaling and receptor endocytosis are modulated by the plasma membrane phosphoinositide lipid phosphatidylinositol-(4, 5)-bisphosphate (PI(4,5)P 2 ). We found that β-arrest...
Article
Possible segregation of plasma membrane (PM) phosphoinositide metabolism in membrane lipid domains is not fully understood. We exploited two differently lipidated peptide sequences, L10 and S15, to mark liquid-ordered, cholesterol-rich (L o ) and liquid-disordered, cholesterol-poor (L d ) domains of the PM, often called raft and nonraft domains, re...
Article
Transmembrane 16A (TMEM16A, anoctamin1), 1 of 10 TMEM16 family proteins, is a Cl ⁻ channel activated by intracellular Ca ²⁺ and membrane voltage. This channel is also regulated by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ]. We find that two splice variants of TMEM16A show different sensitivity to endogenous PI(4,5...
Article
Full-text available
The dynamic metabolism of membrane phosphoinositide lipids involves several cellular compartments including the ER, Golgi, and plasma membrane. There are cycles of phosphorylation and dephosphorylation and of synthesis, transfer, and breakdown. The simplified phosphoinositide cycle comprises synthesis of phosphatidylinositol in the ER, transport, a...
Article
Phosphoinositide lipids regulate many cellular processes and are synthesized by lipid kinases. Type I phosphatidylinositol phosphate 5-kinases (PIP5KIs) generate phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]. Several phosphoinositide-sensitive readouts revealed the nonequivalence of overexpressing PIP5KIβ, PIP5KIγ or Ras association domain...
Article
Introduction: At night, the pineal gland produces the indoleamines, melatonin, N-acetylserotonin (NAS), and N-acetyltryptamine (NAT). Melatonin is accepted as a hormone of night. Could NAS and NAT serve that role too? Methods: Concentration-response measurements with overexpressed human melatonin receptors MT1 and MT2 ; mass spectrometry analysi...
Article
Full-text available
Voltage-sensing phosphatases (VSPs) cleave both 3- and 5-phosphates from inositol phospholipids in response to membrane depolarization. When low concentrations of Ciona intestinalis VSP are expressed in Xenopus laevis oocytes, the 5-phosphatase reaction can be observed during large membrane depolarizations. When higher concentrations are expressed,...
Article
β subunits of high voltage-gated Ca2+ (CaV) channels promote cell-surface expression of pore-forming α1 subunits and regulate channel gating through binding to the α-interaction domain (AID) in the first intracellular loop. We addressed the stability of CaV α1B-β interactions by rapamycin-translocatable CaV β subunits that allow drug-induced seques...
Article
The stability of organic dyes against photobleaching is critical in single-molecule tracking and localization microscopy. Since oxygen accelerates photobleaching of most organic dyes, glucose oxidase is commonly used to slow dye photobleaching by depleting oxygen. As demonstrated here, pyranose-2-oxidase slows bleaching of Alexa647 dye by ∼20-fold....
Article
Full-text available
This essay begins with a description of the founding years of Journal of General Physiology (JGP) and a historical overview of the content of the journal. It then turns to key conceptual articles published in JGP that advanced the field of membrane permeation and ion selectivity. Much of this information comes from reading the online archives of JG...
Chapter
G protein-coupled seven-transmembrane receptors (GPCRs) mediate responses to hormones, metabolites, lipids, and neurotransmitters at the cell membrane, and so they are prominent drug targets. Although many structural, biochemical, cell biological, and biophysical studies made remarkable progress to understand mechanisms of GPCR signaling, there sti...
Data
Custom function to randomize binary particle images written in MATLAB. DOI: http://dx.doi.org/10.7554/eLife.28029.018
Data
Custom software for Ca2+ sparklet detection and analysis written in MATLAB. DOI: http://dx.doi.org/10.7554/eLife.28029.019
Article
Binding of agonists to G-protein–coupled receptors (GPCRs) activates heterotrimeric G proteins and downstream signaling. Agonist-bound GPCRs are then phosphorylated by protein kinases and bound by arrestin to trigger desensitization and endocytosis. Arrestin plays another important signaling function. It recruits and regulates activity of an extrac...
Article
Phosphoinositides are rapidly turning-over phospholipids that play key roles in intracellular signaling and modulation of membrane effectors. Through technical refinements we have improved sensitivity in the analysis of the phosphoinositide PI, PIP, and PIP2 pools from living cells using mass spectrometry. This has permitted further resolution in p...
Article
Full-text available
Extracellular adenosine-5′-triphosphate (ATP) regulates cell death and survival of neighboring cells. The detailed effects are diverse depending on cell types and extracellular ATP concentration. We addressed the effect of ATP on ethanol-induced cytotoxicity in epithelial cells, the cell type that experiences the highest concentrations of alcohol....
Article
Voltage-sensing phosphatases (VSPs) are homologs of phosphatase and tensin homolog (PTEN), a phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] 3-phosphatase. However, VSPs have a wider range of substrates, cleaving 3-phosphate from PI(3,4)P2 and probably PI(3,4,5)P3 as well as 5-phosphate f...
Article
Myo-inositol is an important cellular osmolyte in autoregulation of cell volume and fluid balance, particularly for mammalian brain and kidney cells. We find it also regulates excitability. Myo-inositol is the precursor of phosphoinositides, key signaling lipids including phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. However, whether myo-inosi...
Article
Full-text available
Endoplasmic reticulum–plasma membrane (ER–PM) contact sites play an integral role in cellular processes such as excitation–contraction coupling and store-operated calcium entry (SOCE). Another ER–PM assembly is one tethered by the extended synaptotagmins (E-Syt). We have discovered that at steady state, E-Syt2 positions the ER and Sac1, an integral...
Article
Pinealocytes secrete melatonin at night in response to norepinephrine released from sympathetic nerve terminals in the pineal gland. The gland also contains many other neurotransmitters whose cellular disposition, activity, and relevance to pineal function are not understood. Here we clarify sources and demonstrate cellular actions of the neurotran...
Article
Activated Gq protein-coupled receptors (GqPCRs) can be desensitized by phosphorylation and β-arrestin binding. The kinetics and individual contributions of these two mechanisms to receptor desensitization have not been fully distinguished. Here, we describe the shut off of protease-activated receptor 2 (PAR2). PAR2 activates Gq and phospholipase C...
Article
Full-text available
The pineal gland, an endocrine organ in the brain, synthesizes and secretes the circulating night hormone melatonin throughout the night. The literature states that this hormone is secreted by simple diffusion across the pinealocyte plasma membrane, but a direct quantitative measurement of membrane permeability has not been made. Experiments were d...
Article
Contacts between the endoplasmic reticulum and the plasma membrane (ER-PM junctions) facilitate intracellular communication and are essential to excitation-contraction coupling and store-operated calcium entry (SOCE). We find that they also regulate membrane phosphoinositides, lipids that control ion channels and electrical excitability. We examine...
Article
Full-text available
BK channels are calcium-dependent potassium channels that couple to voltage-gated calcium channels. Because of their calcium dependence, activation curves of BK channels reflect activation curves of their coupling partners. CaV1.3 channels are low-voltage activated voltage-gated calcium channels. We hypothesized that coupling of BK and CaV1.3 chann...
Article
Our basic hypothesis is that mammalian pinealocytes have cycling electrical excitability and Ca²⁺ signalling that may contribute to the circadian rhythm of pineal melatonin secretion. This study asked whether the functional expression of voltage-gated Ca²⁺ channels (CaV channels) in rat pinealocytes is changed by culturing them in noradrenaline (NA...
Article
Full-text available
Levels of nerve growth factor (NGF) are elevated in inflamed tissues. In sensory neurons, increases in NGF augment neuronal sensitivity (sensitization) to noxious stimuli. Here, we hypothesized that NGF also sensitizes sympathetic neurons to proinflammatory stimuli. We cultured superior cervical ganglion (SCG) neurons from adult male Sprague Dawley...
Article
Full-text available
Upon glucose elevation, pancreatic beta-cells secrete insulin in a Ca2+-dependent manner. In diabetic animal models, different aspects of the calcium signaling pathway in beta-cells are altered, but there is no consensus regarding their relative contributions to the development of beta-cell dysfunction. In this study, we compared the increase in cy...
Article
Full-text available
Plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] regulates the activity of many ion channels and other membrane-associated proteins. To determine precursor sources of the PM PI(4,5)P2 pool in tsA-201 cells, we monitored KCNQ2/3 channel currents and translocation of PHPLCδ1 domains as real-time indicators of PM PI(4,5)P2, and t...
Article
Full-text available
G-protein-coupled receptors mediate responses to external stimuli in various cell types. We are interested in the modulation of KCNQ2/3 potassium channels by the Gq-coupled M1 muscarinic (acetylcholine) receptor (M1R). Here, we describe development of a mathematical model that incorporates all known steps along the M1R signaling cascade and accurat...
Article
Melatonin secretion from the pineal gland is triggered by norepinephrine released from sympathetic terminals at night. In contrast, cholinergic and parasympathetic inputs, by activating nicotinic cholinergic receptors (nAChR), have been suggested to counterbalance the noradrenergic input. Here we investigated whether adrenergic signaling regulates...
Article
Sac1 is an integral membrane lipid 4-phosphatase enzyme localized to the endoplasmic reticulum. Sac1 dephosphorylates phosphatidylinositol 4-phosphate (PI(4)P) and has been reported to visit both the Golgi and the plasma membrane transiently. We wanted to determine whether Sac1 influences the supply of plasma membrane (PM) phosphatidylinositol (4,5...
Article
The sympathetic nervous system plays a role during chronic inflammation. Since levels of nerve growth factor (NGF) are high in inflamed tissues and, in sensory neurons, NGF controls nociception by regulating neuronal sensitivity to noxious stimuli, we hypothesize that NGF also sensitizes sympathetic neurons to bradykinin (BK), a proinflammatory pep...
Article
Store-operated Ca(2+) channels (SOCs) are activated by depletion of intracellular Ca(2+) stores following agonist-mediated Ca(2+) release. Previously we demonstrated that Ca(2+) influx through SOCs elicits exocytosis efficiently in pancreatic duct epithelial cells (PDEC). Here we describe the biophysical, pharmacological, and molecular properties o...
Article
Full-text available
Recently, we screened several KV channels for possible dependence on plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2). The channels were expressed in tsA-201 cells and the PI(4,5)P 2 was depleted by several manipulations in whole-cell experiments with parallel measurements of channel activity. In contrast to reports on excised-pat...
Article
Full-text available
Gq-coupled plasma membrane receptors activate phospholipase C (PLC), which hydrolyzes membrane phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). This leads to calcium release, protein kinase C (PKC) activation, and sometimes PIP2 depletion. To understand mechanisms g...
Article
Full-text available
Gq protein–coupled receptors (GqPCRs) of the plasma membrane activate the phospholipase C (PLC) signaling cascade. PLC cleaves the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers diacylgycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), leading to calcium release, protein kinase C (PKC) activation, and in so...
Article
Full-text available
SignificanceElevated cytoplasmic calcium modulates many cellular responses. Two Ca(2+) sources feed most cytoplasmic Ca(2+) elevations, the extracellular space and the endoplasmic reticulum. We found that secretory granules represent another Ca(2+) source that releases Ca(2+) in a physiologically interesting way. We developed a targeted probe for m...
Article
Full-text available
Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) regulates activities of numerous ion channels including inwardly rectifying potassium (K(ir)) channels, KCNQ, TRP, and voltage-gated calcium channels. Several studies suggest that voltage-gated potassium (K(V)) channels might be regulated by PI(4,5)P(2). Wide expression of K(V) channels in differe...
Article
Full-text available
Phosphoinositides (PIs) are lipid components of cell membranes that regulate a wide variety of cellular functions. Here we exploited the blue light-induced dimerization between two plant proteins, cryptochrome 2 (CRY2) and the transcription factor CIBN, to control plasma membrane PI levels rapidly, locally, and reversibly. The inositol 5-phosphatas...
Article
In most eukaryotic cells, microtubules and filamentous actin (F-actin) provide tracks on which intracellular organelles move using molecular motors. Here we report that cytoplasmic movement of both mitochondria and lysosomes is slowed by F-actin meshwork formation in pancreatic duct epithelial cells (PDEC). Mitochondria and lysosomes were labeled w...
Article
Phosphoinositide phospholipids are key membrane signals that activate intrinsic membrane proteins and are loose anchor points for peripheral membrane proteins. They are also precursors for numerous second messengers. This essay reviews historical development, current opinions, and future questions about phosphoinositide signaling.
Article
Full-text available
The β-subunits of voltage-gated Ca(2+) (Ca(V)) channels regulate the functional expression and several biophysical properties of high-voltage-activated Ca(V) channels. We find that Ca(V) β-subunits also determine channel regulation by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP(2)). When Ca(V)1.3, -2.1, or -2.2 channels are...
Article
Plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is required for KCNQ2/3 channel activity. To determine precursor sources of the plasma membrane (PM) PI(4,5)P2 pool in tsA-201 cells, we monitored KCNQ tail currents and YFP-PH(PLC-delta) translocation as real-time indicators of PM PI(4,5)P2, and GFP-OSH1-PH as an indicator of G...
Article
Phosphatidylinositol −4,5-bisphosphate (PI(4,5)P2) is an important regulator of activity of a variety of ion channels including inwardly rectifying potassium channels, KCNQ, TRP, and voltage-gated calcium channels. Several groups have provided evidence that also voltage-gated potassium (Kv) channels might be regulated by PI(4,5)P2. Taking the wide...
Presentation
The four talks in this symposium highlight the dependence of ion channel function on membrane phospholipids and fatty acids. Although of low abundance (1-2%), the phosphoinositide phosphatidylinositol 4,5-bisphosphate (PIP2) is a signature lipid of plasma membranes. The PIP2 lipid aids ion channel function there, and depleting PIP2 can decrease the...
Poster
Gq-coupled plasma membrane receptors modulate cellular functions by activating phospholipase C (PLC), which hydrolyses the membrane lipid phosphatidylinositol (4,5)-bisphosphate (PIP2) into the second messengers inositoltrisphosphate (IP3) and diacylgycerol (DAG). To better understand the mechanisms that govern these partially independent signals w...
Chapter
The sections in this article are:
Article
Full-text available
Adenosine is a candidate modulator of sperm motility in the female reproductive tract that increases sperm flagellar beat frequency in vitro. Past work suggested that this acceleration may involve equilibrative (ENT) and concentrative (CNT) nucleoside transporters. Here we show that Slc29a1 (ENT-1) is the predominant nucleoside transporter expresse...
Article
Full-text available
Phosphoinositides are a family of minority acidic phospholipids in cell membranes. Their principal role is instructional: they interact with proteins. Each cellular membrane compartment uses a characteristic species of phosphoinositide. This signature phosphoinositide attracts a specific complement of functionally important, loosely attached periph...
Article
Modulation of voltage-gated Ca(2+) channels controls activities of excitable cells. We show that high-voltage activated Ca(2+) channels are regulated by membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)) with different sensitivities. Plasma membrane PIP(2) depletion by rapamycin-induced translocation of an inositol lipid 5-phosphatase or by a...
Article
Full-text available
Exocytosis is evoked by intracellular signals, including Ca(2+) and protein kinases. We determined how such signals interact to promote exocytosis in exocrine pancreatic duct epithelial cells (PDECs). Exocytosis, detected using carbon-fiber microamperometry, was stimulated by [Ca(2+)](i) increases induced either through Ca(2+) influx using ionomyci...
Article
Full-text available
We are deeply disturbed by the recent escalation of political assaults on scientists in general and on climate scientists in particular. All citizens should understand some basic scientific facts. There is always some uncertainty associated with scientific conclusions; science never absolutely proves anything. When someone says that society should...
Article
Full-text available
G protein-coupled receptors (GPCRs) mediate responses to external stimuli in various cell types. Early events, such as the binding of ligand and G proteins to the receptor, nucleotide exchange (NX), and GTPase activity at the Galpha subunit, are common for many different GPCRs. For G(q)-coupled M(1) muscarinic (acetylcholine) receptors (M(1)Rs), we...
Article
Full-text available
The signaling phosphoinositide phosphatidylinositol 4,5-bisphosphate (PIP(2)) is synthesized in two steps from phosphatidylinositol by lipid kinases. It then interacts with KCNQ channels and with pleckstrin homology (PH) domains among many other physiological protein targets. We measured and developed a quantitative description of these metabolic a...
Article
Full-text available
Pancreatic islet cells use neurotransmitters such as l-glutamate to regulate hormone secretion. We determined which cell types in mouse pancreatic islets express ionotropic glutamate receptor channels (iGluRs) and describe the detailed biophysical properties and physiological roles of these receptors. Currents through iGluRs and the resulting membr...
Article
Adenosine is a candidate modulator of motility of spermatozoa as they progress through the female reproductive tract. Past work demonstrated that the adenosine analog 2-chloro-deoxyadenosine (Cl-dAdo) accelerates the flagellar beat rate of mouse sperm by a cAMP/PKA-mediated pathway with a pharmacological profile suggestive of a Slc29a (ENT) equilib...