Byung-Chang Suh

Daegu Gyeongbuk Institute of Science and Technology | DGIST · Department of Brain and Cognitive Sciences

G protein-coupled receptors (GPCRs) regulate diverse intracellular signaling pathways through the activation of heterotrimeric G proteins. However, the effects of the sequential activation-deactivation cycle of G protein on the conformational changes of GPCRs remains unknown. By developing a Förster resonance energy transfer (FRET) tool for human M...

Normal alcohols (n-alcohols) can induce anesthetic effects by acting on neuronal ion channels. Recent studies have revealed the effects of n-alcohols on various ion channels; however, the underlying molecular mechanisms remain unclear. Here, we provide evidence that long-chain n-alcohols have dual effects on Kv7.2/7.3 channels, resulting in channel...

High-voltage-activated Ca ²⁺ (Ca V ) channels that adjust Ca ²⁺ influx upon membrane depolarization are differentially regulated by phosphatidylinositol 4,5-bisphosphate (PIP 2 ) in an auxiliary Ca V β subunit-dependent manner. However, the molecular mechanism by which the β subunits control the PIP 2 sensitivity of Ca V channels remains unclear. B...

Significance Up-regulation of the M-type KCNQ2/KCNQ3 channels from late fetal life to early infancy is important for normal development and functional maturation of nervous systems in the brain. However, detailed mechanisms for the early regulation of KCNQ2/3 expression remain unclear. Here, we report that select miR-106b microRNA (miRNA) family me...

TMEM16A is a Ca2+-activated Cl− channel that controls broad cellular processes ranging from mucus secretion to signal transduction and neuronal excitability. Recent studies have reported that membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is an important cofactor that allosterically regulates TMEM16A channel activity. Howev...

Significance Lipids of bilayer membranes can segregate laterally into distinct liquid phases of different composition called liquid ordered and liquid disordered, and corresponding in the plasma membrane of living cells to nanodomains called raft and nonraft domains. Using Förster resonance energy transfer and genetically expressible protein probes...

Ethanol often causes critical health problems by altering the neuronal activities of the central and peripheral nerve systems. One of the cellular targets of ethanol is the plasma membrane proteins including ion channels and receptors. Recently, we reported that ethanol elevates membrane excitability in sympathetic neurons by inhibiting Kv7.2/7.3 c...

Significance Transmembrane 16A (TMEM16A, anoctamin1), a Cl ⁻ channel activated by intracellular Ca ²⁺ and membrane voltage, displays several distinctive biophysical properties based on differential splicing of alternative exons. Recently, this channel was reported to be regulated by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [P...

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...

Alcohol causes diverse acute and chronic symptoms that often lead to critical health problems. Exposure to ethanol alters the activities of sympathetic neurons that control the muscles, eyes, and blood vessels in the brain. Although recent studies have revealed the cellular targets of ethanol, such as ion channels, the molecular mechanism by which...

Acid-sensing ion channels (ASICs), sensory molecules that continuously monitor the concentration of extracellular protons and initiate diverse intracellular responses through an influx of cations, are assembled from six subtypes that can differentially combine to form various trimeric channel complexes and elicit unique electrophysiological respons...

Significance Voltage-gated Ca ²⁺ (Ca V ) channels have an α1-α2δ core complexed with one of several alternative β subunits. Contradictory evidence says that, once bound, ( i ) a β subunit is permanently associated with the α1-α2δ core or ( ii ) that it is free to be exchanged for other β subunits. We designed rapamycin-translocatable Ca V β subunit...

Voltage-gated calcium (CaV) channels mediate diverse essential physiological functions through membrane depolarization-induced Ca2+ influx. Malfunction of CaV channels causes various pathophysiological disorders. A wide range of cellular signals, including phosphoinositides, auxiliary CaV $beta$ subunits, Ca2+/calmodulin, and phosphorylation, are c...

Recently, we showed that the HOOK region of the β2 subunit electrostatically interacts with the plasma membrane and regulates the current inactivation and phosphatidylinositol 4,5-bisphosphate (PIP2) sensitivity of voltage-gated Ca²⁺ (CaV) 2.2 channels. Here, we report that voltage-dependent gating and current density of the CaV2.2 channels are als...

The β subunit of voltage-gated Ca ²⁺ (Ca V ) channels plays an important role in regulating gating of the α1 pore-forming subunit and its regulation by phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Subcellular localization of the Ca V β subunit is critical for this effect; N-terminal–dependent membrane targeting of the β subunit slows inactivatio...

Acid-sensing ion channels (ASICs) are proton-activated cation channels that play important roles as typical proton sensors during pathophysiological conditions and normal synaptic activities. Among the ASIC subunits, ASIC2a and ASIC2b are alternative splicing products from the same gene, ACCN1. It has been shown that ASIC2 isoforms have differentia...

Voltage-gated calcium (Cav) channels, which are regulated by membrane potential, cytosolic Ca²⁺, phosphorylation, and membrane phospholipids, govern Ca²⁺ entry into excitable cells. Cav channels contain a pore-forming a1 subunit, an auxiliary α2δ subunit, and a regulatory b subunit, each encoded by several genes in mammals. In addition to a domain...

The PI(4,5)P2 level in the plasma membrane is dynamically regulated by cytoplasmic ATP production and receptor-mediated transmembrane signaling cascades. In this issue of Cell Chemical Biology, Xie et al. (2016) use optogenetics to micro-manipulate membrane PI(4,5)P2 and reveal how acute PI(4,5)P2 changes can alter intracellular Ca²⁺ dynamics and i...

Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the nervous system. Proton sensing by ASICs has been known to mediate pain, mechanosensation, taste transduction, learning and memory, and fear. In this study, we investigated the differential subcellular localization of ASIC2a and ASIC3 in heterologous expressio...

Significance Phosphatase and tensin homolog (PTEN) is a phosphatidylinositol 3,4-bisphosphate [PI(3,4)P 2 ] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] 3-phosphatase that plays important roles in cell polarization, division, and development as well as in tumor suppression. Voltage-sensing phosphatases (VSPs) are PTEN family members...

Voltage-gated Ca(2+) (CaV) channels are dynamically modulated by G protein-coupled receptors (GPCR). The M1 muscarinic receptor stimulation is known to enhance CaV2.3 channel gating through the activation of protein kinase C (PKC). Here, we found that M1 receptors also inhibit CaV2.3 currents when the channels are fully activated by PKC. In whole-c...

Voltage-gated calcium (CaV) channels are responsible for Ca(2+) influx in excitable cells. As one of the auxiliary subunits, the CaV β subunit plays a pivotal role in the membrane expression and receptor modulation of CaV channels. In particular, the subcellular localization of the β subunit is critical for determining the biophysical properties of...

The auxiliary β subunit plays an important role in the regulation of voltage-gated calcium (CaV) channels. Recently, it was revealed that β2e associates with the plasma membrane through an electrostatic interaction between N-terminal basic residues and anionic phospholipids. However, a molecular-level understanding of β-subunit membrane recruitment...

Transient receptor potential ankyrin1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) are members of the TRP superfamily of structurally related, nonselective cation channels and mediators of several signaling pathways. Previously, we identified methyl syringate as an hTRPA1 agonist with efficacy against gastric emptying. The aim of th...

High voltage-activated Ca(2+) (CaV) channels are protein complexes containing pore-forming α1 and auxiliary β and α2δ subunits. The subcellular localization and membrane interactions of the β subunits play a crucial role in regulating CaV channel inactivation and its lipid sensitivity. Here, we investigated the effects of membrane phosphoinositide...

Protons are released in pain-generating pathological conditions such as inflammation, ischemic stroke, infection, and cancer. During normal synaptic activities, protons are thought to play a role in neurotransmission processes. Acid-sensing ion channels (ASICs) are typical proton sensors in the central nervous system (CNS) and the peripheral nervou...

Specific protein-phosphoinositide (PI) interactions are known to play a key role in the targeting of proteins to specific cellular membranes. Investigation of these interactions would be greatly facilitated if GFP-fusion proteins expressed in mammalian cells and used for their subcellular localization could also be employed for in vitro lipid bindi...

G protein-coupled receptors (GPCRs) signal through molecular messengers, such as Gβγ, Ca(2+), and phosphatidylinositol 4,5-bisphosphate (PIP2), to modulate N-type voltage-gated Ca(2+) (CaV2.2) channels, playing a crucial role in regulating synaptic transmission. However, the cellular pathways through which GqPCRs inhibit CaV2.2 channel current are...

Phosphodiesterases (PDEs) play key roles in cAMP compartmentalization, which is required for intracellular signaling processes, through specific subcellular targeting. Previously, we showed that the long and short forms of Aplysia PDE4 (ApPDE4), which are localized to the membranes of distinct subcellular organelles, play key roles in 5-hydroxytryp...

TRPV1t, a variant of the transient receptor potential vanilloid-1 (TRPV1) has been proposed as a constitutively active, non-selective cation channel as a putative amiloride-insensitive salt taste receptor and shares many properties with TRPV1. Based on our previous chorda tympani taste nerve recordings in rodents and human sensory evaluations, we p...

N-type voltage-gated Ca2+ (CaV2.2) channels, which enable synaptic transmission by triggering neurotransmitter release, are tightly modulated by G protein-coupled receptors (GPCRs) via several downstream signaling messengers, such as G, calmodulin, arachidonic acid and PIP2. However, the molecular mechanism by which Gq/11-coupled receptors (GqPCR...

Extracellular acidification occurs not only in pathological conditions such as inflammation and brain ischemia, but also in normal physiological conditions such as synaptic transmission. Acid-sensing ion channels (ASICs) can detect a broad range of physiological pH changes during pathological and synaptic cellular activities. ASICs are voltage-inde...

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...

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...

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...

Ubiquitously expressed Mg(2+)-inhibitory cation (MIC) channels are permeable to Ca2+ and Mg2+ and are essential for cell viability. When membrane cholesterol level was increased by pre-incubating cells with a water-soluble form of cholesterol, the endogenous MIC current in HEK293 cells was negatively regulated. The application of phosphatidylinosit...

Voltage-sensitive phosphatases (VSPs) have a voltage sensor linked to a phosphoinositide (PI) 5-phosphatase, which hydrolyzes plasma membrane PI-(4,5)-bisphosphate (PIP2) to PI(4)P (Iwasaki, PNAS 105, 7970). We used PIP2 hydrolysis by VSP from Ciona intestinalis (ci-VSP) and zebrafish (dr-VSP) to better understand PIP2 binding and resynthesis. PIP2...

The regulatory mode of the P2Y11 purinoceptor-mediated signalling cascades towards phospholipase C and adenylyl cyclase was studied in HL-60 promyelocytes. Treatment with the potent P2Y11 receptor activator dATP evoked an elevated intracellular Ca2+ concentration ([Ca2+]i) and inositol 1,4,5-trisphosphate (IP3) production that was sustained for lon...

The prostaglandin-evoked cAMP production was studied in human neuroblastoma SK-N-BE(2)C cells during neuronal differentiation induced by all-trans retinoic acid. The incubation with 5 µm all-trans retinoic acid for 4–6 days promoted neurite outgrowth of cells. After differentiation, prostaglandin E2 (PGE2)-induced cAMP production was dramatically i...

Phosphatidylinositol 4,5-bisphosphate (PIP2) is a minority phospholipid of the inner leaflet of plasma membranes. Many plasma membrane ion channels and ion transporters require PIP2 to function and can be turned off by signaling pathways that deplete PIP2. This review discusses the dependence of ion channels on phosphoinositides and considers possi...

Activity of KCNQ (Kv7) channels requires binding of phosphatidylinositol 4,5-bisphosphate (PIP(2)) from the plasma membrane. We give evidence that Mg(2+) and polyamines weaken the KCNQ channel-phospholipid interaction. Lowering internal Mg(2+) augmented inward and outward KCNQ currents symmetrically, and raising Mg(2+) reduced currents symmetricall...

Activation of phospholipase C (PLC) through G-protein-coupled receptors produces a large number of second messengers and regulates many physiological processes. Many membrane proteins including ion channels require the phosphoinositide phosphatidylinositol 4,5-bisphosphate (PIP(2)) to function. Activation of PLC can shut down their activity if it d...

To resolve the controversy about messengers regulating KCNQ ion channels during phospholipase C–mediated suppression of current, we designed translocatable enzymes that quickly alter the phosphoinositide composition of the plasma membrane after application of a chemical cue. The KCNQ current falls rapidly to zero when phosphatidylinositol 4,5-bisph...

Some ion channels are regulated by inositol phospholipids and by the products of cleavage by phospholipase C (PLC). KCNQ channels (Kv7) require membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)) and are turned off when muscarinic receptors stimulate cleavage of PIP(2) by PLC. We test whether diacylglycerols are also important in the regulation...

We have further tested the hypothesis that receptor-mediated modulation of KCNQ channels involves depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphoinositide-specific phospholipase C (PLC). We used four parallel assays to characterize the agonist-induced PLC response of cells (tsA or CHO cells) expressing M1 muscarinic receptors:...

We have further tested the hypothesis that receptor-mediated modulation of KCNQ channels involves depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphoinositide-specific phospholipase C (PLC). We used four parallel assays to characterize the agonist-induced PLC response of cells (tsA or CHO cells) expressing M1 muscarinic receptors:...

ATP is co-localized with norepinephrine at the sympathetic nerve terminals and may be released simultaneously upon neuronal stimulation, which results in activation of purinergic receptors. To examine whether leptin synthesis and lipolysis are influenced by P2 purinergic receptor activation, the effects of ATP and other nucleotides on leptin secret...

Phosphatidylinositol 4,5-bisphosphate is a signaling phospholipid of the plasma membrane that has a dynamically changing concentration. In addition to being the precursor of inositol trisphosphate and diacylglycerol, it complexes with and regulates many cytoplasmic and membrane proteins. Recent work has characterized the regulation of a wide range...

Receptor-mediated modulation of KCNQ channels regulates neuronal excitability. This study concerns the kinetics and mechanism of M1 muscarinic receptor-mediated regulation of the cloned neuronal M channel, KCNQ2/KCNQ3 (Kv7.2/Kv7.3). Receptors, channels, various mutated G-protein subunits, and an optical probe for phosphatidylinositol 4,5-bisphospha...

Cyclin-dependent kinase 5 (Cdk5) is a serine-threonine kinase that is activated by the binding of p35 or p39 regulatory protein. Cdk5 and p35 are highly localized in the growth cone of cultured neurons, and Cdk5 activity is associated with neurite outgrowth. Here we report evidence on the functional involvement of Cdk5 kinase in regenerating periph...

Insulin secretion is known to depend on an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)). However, recent studies have suggested that insulin secretion can also be evoked in a Ca(2+)-independent manner. In the present study we show that treatment of intact mouse islets and RINm5F cells with protein kinase C (PKC) activator phorbol 12...

Extracellular nucleotides exert a variety of biological actions through several kinds of P2 receptors in many tissues and cell types. We found that treatment with nucleotides increases intracellular Ca2+ concentration ([Ca2+]i) in SK-N-BE(2)C human neuroblastoma cells with a following order of potency: UDP > UTP > ADP > ATP. Reverse transcription-p...

Suppression of M current channels by muscarinic receptors enhances neuronal excitability. Little is known about the molecular mechanism of this inhibition except the requirement for a specific G protein and the involvement of an unidentified diffusible second messenger. We demonstrate here that intracellular ATP is required for recovery of KCNQ2/KC...

The adenosine receptor in mouse pinealocytes was identified and characterized using pharmacological and physiological approaches. Expression of the two adenosine receptor subtypes A2B and A3 was detected in mouse pineal glands and PGT-β cells by polymerase chain reaction and nucleotide sequencing. Adenosine and 5′-N-ethylcarboxamidoadenosine (NECA)...

Histamine, through H2 receptors, triggers a prominent rise in intracellular free Ca2+ concentration ([Ca2+]i) in addition to an elevation of cAMP level in HL-60 promyelocytes. Here we show that the histamine-induced [Ca2+]i rise was due to influx of Ca2+ from the extracellular space, probably through nonselective cation channels, as incubation of t...

Rhythmic noradrenergic signaling from the hypothalamic clock in the suprachiasmatic nucleus to the pineal gland causes an increase in intracellular cAMP which regulates the circadian fluctuation of melatonin synthesis. The activation of phospholipase C (PLC)-coupled P2Y2 receptors upon treatment with ATP and UTP exclusively inhibited the isoprotere...

The P2X7 receptor, which induces cation channel opening imparting significant permeability to Ca2+ and pore formation with changes in the plasma membrane potential, has been known to be rather restrictedly expressed in cells of the macrophage lineage including dendrites, mature macrophages, and microglial cells. However, we show here that the P2X7...

d- and l-myo-inositol 1,2,4,5-tetrakisphosphate (Ins(1,2,4,5)P4) were investigated for their ability to bind to the d-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) receptor in a bovine adrenal cortical membrane fraction, to mobilize intracellular Ca2+ stores in Xenopus oocytes, and to bind to the rat brain Ins(1,4,5)P3 3-kinase overexpressed and...

We investigated the effect of chlorpromazine (CPZ), a phenothiazine neuroleptic, on catecholamine secretion in rat pheochromocytoma (PC12) cells. CPZ inhibited [3H]norepinephrine ([3H]NE) secretion induced by 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), an agonist of nicotinic acetylcholine receptors (nAChRs) with an ic50 value of 1.0 ± 0.2 μM....