The BKCa channel (large-conductance calcium-activated potassium channel) is expressed on various tissues and is involved in smooth muscle relaxation. The channel is highly expressed on urinary bladder smooth muscle (UBSM) cells and regulates the repolarization phase of the spontaneous action potentials that control muscle contraction. To discover novel chemical activators of the BKCa channel, we screened

The family of GABAA receptors is an important drug target group in the treatment of sleep disorders, anxiety, epileptic seizures and many others. The most frequent GABAA receptor subtype is composed of two α, two β and one γ2-subunit, while the nature of the α-subunit critically determines the properties of the benzodiazepine binding site of those receptors. Nearly all of the clinically relevant drugs

Equilibrative nucleoside transporters (ENT) 1 and 2 facilitate nucleoside transport across the blood-testis barrier (BTB). Improving drug entry into the testes with drugs that use endogenous transport pathways may lead to more effective treatments for diseases within the reproductive tract. In this study, CRISPR/Cas9 was used to generate HeLa cell lines in which ENT expression was limited to ENT1 or

Overdose of acetaminophen (APAP) has become one of the most reasons to induce acute liver failure. Macrophage-inducible C-type lectin (Mincle) acts as a key moderator in immune responses by recognizing spliceosome associated protein 130 (SAP130), which is an endogenous ligand released by necrotic cells. This study aims to explore the function of Mincle in APAP-induced hepatotoxicity. Wild-type (WT)

Cardiac fibrosis is characterized by accumulation and activation of fibroblasts and excessive production of extracellular matrix, which results in myocardial stiffening and eventually leads to heart failure. While previous work suggests that protein kinase C (PKC) isoforms play a role in cardiac fibrosis and remodeling, the results are conflicting. Moreover, the potential of targeting PKC with pharmacological

A first-in- class cannabinoid analog called lenabasum that is a CB2 agonist is being developed as an inflammation-resolving drug candidate. Thus far specific therapeutic targets include scleroderma, cystic fibrosis, dermatomyositis and lupus all of which represent unmet medical needs. Two somewhat independent molecular mechanisms for this type of action are here proposed. Both pathways initially involve

Synaptic GABAA receptors are alternately exposed to short pulses of a high, millimolar concentration of GABA and prolonged periods of low, micromolar concentration of the transmitter. Prior work has indicated that exposure to micromolar concentrations of GABA can both activate the postsynaptic receptors generating sustained low-amplitude current and desensitize the receptors, thereby reducing the peak

Since their discovery in the mid-1990s, regulator of G protein signaling (RGS) proteins have emerged as key regulators of signaling through G protein–coupled receptors. Among the over 20 known RGS proteins, RGS2 has received increasing interest as a potential therapeutic drug target with broad clinical implications. RGS2 is a member of the R4 subfamily of RGS proteins and is unique in that it is selective

Regulator of G protein signaling (RGS) proteins are multifunctional proteins expressed in peripheral and neuronal cells, playing critical roles in development, physiologic processes, and pharmacological responses. RGS proteins primarily act as GTPase accelerators for activated Gα subunits of G-protein coupled receptors, but they may also modulate signal transduction by several other mechanisms. Over

Parkinson disease (PD) is a devastating, largely nonfamilial, age-related disorder caused by the progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Release of DA from these neurons into the dorsal striatum is crucial for regulating movement and their loss causes PD. Unfortunately, the mechanisms underlying SNc neurodegeneration remain unclear, and currently there

The currents of α7 nicotinic acetylcholine receptors activated by acetylcholine (ACh) are brief. The channel has high permeability to calcium relative to monovalent cations and shows inward rectification. It has been previously noted that in the presence of positive allosteric modulators (PAMs), currents through the channels of α7 receptors differ from normal α7 currents both in sensitivity to specific

Regulator of G protein signaling (RGS) proteins are negative modulators of G protein signaling that have emerged as promising drug targets to improve specificity and reduce side effects of G protein–coupled receptor–related therapies. Several small molecule RGS protein inhibitors have been identified; however, enhancing RGS protein function is often more clinically desirable but presents a challenge

Degeneration of photoreceptors caused by excessive illumination, inherited mutations or aging are the principal pathology of blinding diseases. Pharmacological compounds that stabilize the visual receptor, rhodopsin, and modulate the cellular pathways triggering death of photoreceptors could avert this pathology. Interestingly, flavonoids can modulate the cellular processes such as oxidative stress

Aberrant activation of Wnt/β-catenin axis occurs in several gastrointestinal malignancies due to inactivating mutations of APC (in colorectal cancer) or activating mutations of β-catenin itself (in hepatocellular carcinoma [HCC]). These lead to β-catenin stabilization, increase in β-catenin/TCF-mediated transcriptional activation and target gene expression, many of which are involved in tumor progression

Tetramethylenedisulfotetramine (TETS) is a so-called "caged" convulsant, that is responsible for thousands of accidental and malicious poisonings. Similar to the widely used GABAA antagonist picrotoxinin, TETS has been proposed to bind to the non-competitive antagonist (NCA) site in the pore of the gamma-aminobutyric acid (GABA) receptor channel. However, the TETS binding site has never been experimentally

ACE2 has emerged as a double agent in the COVID-19 ordeal being physiologically protective yet conducive of viral infection. The identification of ACE2 in as many as 72 tissues suggests that extra-pulmonary invasion and damage is likely, which indeed has already been demonstrated by cardiovascular and gastro-intestinal symptoms. On the other hand, identifying ACE2 dysregulation in patients with co-morbidities

N-ribosyldihydronicotinamide:quinone oxidoreductase 2 (NQO2/QR2, Enzyme Commission number 1.10.99.2) is a cytosolic enzyme, abundant in the liver and variably expressed in mammalian tissues. Cloned 30 years ago, it was characterized as a flavoenzyme catalyzing the reduction of quinones and pseudoquinones. To do so, it uses exclusively N-alkyl nicotinamide derivatives, without being able to recognize

CYP2A enzymes metabolically inactivate nicotine and activate tobacco-derived procarcinogens (e.g. NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone). Smoking decreases nicotine clearance, and chronic nicotine reduces hepatic CYP2A activity. However, little is known about the impact of smoking or nicotine on the expression of CYP2A in the lung. We investigated 1) the levels of human lung CYP2A mRNA

This study investigated the roles of transient receptor potential (TRP) ankyrin-1 (TRPA1) and TRP vanilloid-3 (TRPV3) in regulating endoplasmic reticulum stress (ERS) and cytotoxicity in human bronchial epithelial cells (HBECs) treated with pneumotoxic wood smoke particulate matter (WSPM) and chemical agonists of each channel. Functions of TRPA1 and TRPV3 in pulmonary epithelial cells remain largely

The CXCL12 system is central to the development of many organs and is further crucially engaged in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders. This disease-associated role presently focuses major interest on the two CXCL12 receptors, CXCR4 and atypical chemokine receptor 3 (ACKR3)/CXCR7, as promising therapeutic targets. Major obstacles in these ongoing

The Notch family consists of four highly conserved transmembrane receptors. The release of the active intracellular domain requires the enzymatic activity of γ-secretase. Notch is involved in embryonic development and in many physiologic processes of normal cells, in which it regulates growth, apoptosis, and differentiation. Notch1, a member of the Notch family, is implicated in many types of cancer

The prototypical member of the receptor-inactivating kappa opioid receptor (KOR) antagonists, norbinaltorphimine (norBNI), produces prolonged receptor inactivation by a cJun kinase mechanism. These antagonists have potential therapeutic utility in the treatment of stress disorders; however, additional preclinical characterization is necessary to understand important aspects of their action. In this

The human CYP2C9 plays a crucial role in the metabolic clearance of a wide range of clinical therapeutics. The *2 allele is a prevalent genetic variation in CYP2C9 that is found in various populations. A marked reduction of catalytic activity toward many important drug substrates has been demonstrated by CYP2C9*2, which represents an amino acid variation at position 144 from arginine to cysteine. The

Eukaryotic initiation factor 2α kinase general control non-derepressible 2 (GCN2) drives cellular adaptation to amino acid limitation by activating the integrated stress response that induces activating transcription factor 4 (ATF4). Here, we found that a multi-kinase inhibitor, GZD824, which we identified using a cell-based assay with ATF4 immunostaining, inhibited the GCN2 pathway in cancer cells

Protein tyrosine phosphatase 4A3 (PTP4A3) is frequently overexpressed in human solid tumors and hematological malignancies and is associated with tumor cell invasion, metastasis, and a poor patient prognosis. Several potent, selective, and allosteric small molecule inhibitors of PTP4A3 were recently identified. A lead compound in the series, JMS-053 (7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione)

The μ-opioid receptor gene undergoes extensive alternative splicing to generate an array of splice variants. One group of splice variants excludes the first transmembrane (TM) domain and contains six TM domains. These 6TM variants are essential for the action of a novel class of analgesic drugs, including 3-iodobenzoyl-6β-naltrexamide, which is potent against a spectrum of pain models without exhibiting

Human ether-a-go-go–related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium current (IKr) important for repolarization of cardiac action potentials. Drug-induced disruption of hERG channel function is a main cause of acquired long QT syndrome, which can lead to ventricular arrhythmias and sudden death. Illicit fentanyl use is associated with sudden

Based on studies using mutations of the µ-opioid receptor (MOR), phosphorylation of multiple sites on the C-terminus has been recognized as a critical step underlying acute desensitization and the development of cellular tolerance. The aim of this study is to explore which kinases mediate desensitization of MOR in brain slices from drug-naïve and morphine-treated animals. Whole-cell recordings from

Opioids are some of the most potent analgesics available. However, their effectiveness is limited by the development of analgesic tolerance. Traditionally, tolerance was thought to occur by termination of μ-opioid receptor (MOR) signaling via desensitization and internalization. Contradictory findings led to a more recent proposal that sustained MOR signaling caused analgesic tolerance. However, this

Opioid receptors (ORs) convert extracellular messages to signaling events by coupling to the heterotrimeric G proteins, Gα•βγ. Classic pharmacological methods, such as [35S]GTPγS binding and inhibition of cyclic AMP production, allow for general opioid characterization, but they are subject to the varying endogenous Gα proteins in a given cell type. Bioluminescence resonance energy transfer (BRET)

Endogenous opioid peptides in the amygdala regulate many of our behaviors and emotional responses. In particular, the endogenous opioid enkephalin plays a significant role in regulating amygdala activity, but its action is strongly limited by peptidases, which degrade enkephalin into inactive fragments. Inhibiting peptidases may be an attractive method to enhance endogenous opioid signaling; however

For decades the broad role of opioids in addiction, neuropsychiatric disorders, and pain states has been somewhat well established. However, in recent years, with the rise of technological advances, not only is the existing dogma being challenged, but we are identifying new disease areas in which opioids play a critical role. This review highlights four new areas of exploration in the opioid field

The powerful analgesic effects of opioid drugs have captivated the interest of physicians and scientists for millennia, and the ability of opioid drugs to produce serious undesired effects has been recognized for a similar period of time (Kieffer and Evans, 2009). Many of these develop progressively with prolonged or repeated drug use and then persist, motivating particular interest in understanding

Evidence from several novel opioid agonists and knockout animals suggests that improved opioid therapeutic window, notably for analgesia versus respiratory depression, is a result of ligand bias downstream of activation of the µ-opioid receptor (MOR) toward G protein signaling and away from other pathways, such as arrestin recruitment. Here, we argue that published claims of opioid bias based on application

This brief review covers concepts in opioid pharmacology that were promoted during the period leading up to the establishment of the International Narcotics Research Conference (INRC) in the early 1970s and the discovery of endogenous opioid peptides in 1975. The founders of INRC, meeting together during the International Union of Pharmacology meeting in Basel in 1969, recognized that the time was

The International Narcotics Research Conference (INRC) has a rich history of uniting the most creative minds across the fields of chemistry, pharmacology, physiology, and behavior in the study of opioids. The Conference has been a forum for sharing knowledge, discussing controversies, introducing innovative research, and announcing landmark discoveries. In this perspective for the Special Issue commemorating

In the past 50 years, scientists have made considerable strides toward understanding how opioids act. This special issue of Molecular Pharmacology celebrates these 50 years of opioid research and the role that the International Narcotics Research Conference has played in driving this research, by bringing together review and original research articles that present historical highlights, the current

Ryanodine receptor (RYR) mutations confer stress-triggered malignant hyperthermia (MH) susceptibility. Dietary caffeine (CAF) is the most commonly consumed psychoactive compound by humans. CAF-triggered Ca2+ release and its influences on skeletal muscle contractility are widely used as experimental tools to study RYR function/dysfunction and diagnose MH susceptibility. We hypothesize that dietary CAF

For decades, traditional drug discovery has used natural product and synthetic chemistry approaches to generate libraries of compounds, with some ending as promising drug candidates. A complementary approach has been to adopt the concept of biomimicry of natural products and metabolites so as to improve multiple drug-like features of the parent molecule. In this effort, promiscuous and weak interactions

Epibatidine is a potent analgetic agent with very high affinity for brain nicotinic acetylcholine receptors (nAChR). We determined the activity profiles of three epibatidine derivatives, RTI-36, RTI-76, and RTI-102, which have affinity for brain nAChR equivalent to that of epibatidine but reduced analgetic activity. RNAs coding for nAChR monomeric subunits and/or concatamers were injected into Xenopus

Cross talk between both pre- and postsynaptic components of glutamatergic neurotransmission plays a crucial role in orchestrating a multitude of brain functions, including synaptic plasticity and motor planning. Metabotropic glutamate receptor (mGluR) 5 exhibits promising therapeutic potential for many neurodevelopmental and neurodegenerative disorders as a consequence of its modulatory control over

Muscimol is a psychoactive isoxazole derived from the mushroom Amanita muscaria and a potent orthosteric agonist of the GABAA receptor. The binding of [3H]muscimol has been used to evaluate the distribution of GABAA receptors in the brain, and studies of modulation of [3H]muscimol binding by allosteric GABAergic modulators such as barbiturates and steroid anesthetics have provided insight into the

Many synthetic compounds to which we attribute specific activities are produced as racemic mixtures of stereoisomers, and it may be that all the desired activity comes from a single enantiomer. We have previously shown this to be the case with the α7 nicotinic acetylcholine receptor positive allosteric modulator (PAM) 3a,4,5,9b-Tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide

The ρ1 GABAA receptor is prominently expressed in the retina and is present at lower levels in several brain regions and other tissues. Although the ρ1 receptor is insensitive to many anesthetic drugs that modulate the heteromeric GABAA receptor, it maintains a rich and multifaceted steroid pharmacology. The receptor is negatively modulated by 5β-reduced steroids, sulfated or carboxylated steroids

Human cytochrome P450 (P450) CYP2B6 undergoes nitric oxide (NO)-dependent proteasomal degradation in response to the NO donor dipropylenetriamine NONOate (DPTA) and biological NO in HeLa and HuH7 cell lines. CYP2B6 is also down-regulated by NO in primary human hepatocytes. We hypothesized that NO or derivative reactive nitrogen species may generate adducts of tyrosine and/or cysteine residues, causing

In medium-size, spiny striatal neurons of the direct pathway, dopamine D1- and adenosine A1-receptors are co-expressed and are mutually antagonistic. Recently, a mutation in the gene encoding the A1-receptor (A1R-G279S7.44) was identified in an Iranian family: two affected off-springs suffered from early onset L-DOPA-responsive Parkinson's disease. The link between the mutation and the phenotype is

Crosstalk between both pre- and post-synaptic components of glutamatergic neurotransmission plays a crucial role in orchestrating a multitude of brain functions including synaptic plasticity and motor planning. Metabotropic glutamate receptor 5 (mGluR5) exhibits a promising therapeutic potential for many neurodevelopmental and neurodegenerative disorders, as the consequence of its modulatory control