PubMed Health⌕ Search

Biomedical subjects

Uhtaek Oh

Publications and source records attributed to Uhtaek Oh.

28 records · Page 2Linked to original sources
PubMed2003

N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues: novel potent and high affinity antagonists and partial antagonists of the vanilloid receptor.

Isosteric replacement of the phenolic hydroxyl group in potent vanilloid receptor (VR1) agonists with the alkylsulfonamido group provides a series of compounds which are effective antagonists to the action of the capsaicin on rat VR1 heterologously expressed in Chinese hamster ovary (CHO) cells. In particular, compound 61, N-[2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl]-N'-[3-fluoro-4-(methylsulfonylamino)benzyl]thiourea was a full antagonist against capsaicin, displayed a K(i) value of 7.8 nM (compared to 520 nM for capsazepine and 4 nM for 5-iodoRTX), and showed excellent analgesic activity in mice. Structure-activity analysis of the influence of modifications in the A- and C-regions of 4-methylsulfonamide ligands on VR1 agonism/antagonism indicated that 3-fluoro substitution in the A-region and a 4-tert-butylbenzyl moiety in the C-region favored antagonism, whereas a 3-methoxy group in the A-region and 3-acyloxy-2-benzylpropyl moieties in the C-region favored agonism.

Analgesics↗
PubMed2003

Essential role of mitochondrial permeability transition in vanilloid receptor 1-dependent cell death of sensory neurons.

Capsaicin causes pain by activating VR1, a cloned capsaicin receptor, in sensory neurons. After the initial excitatory responses, capsaicin produces prolonged analgesia, presumably because of the neurotoxic effect that leads to the death of sensory neurons. However, the mechanism underlying capsaicin-induced cell death of sensory neurons is not known. Here we report that capsaicin induces cell death in VR1-expressing sensory neurons and VR1-transfected human embryonic kidney cells. Cell death of sensory neurons induced by capsaicin is accompanied by DNA fragmentation, TUNEL staining, and shrinkage of the nucleus in a caspase-dependent manner, indicating the apoptotic nature of the cell death. Mitochondrial permeability transition is likely to be a major component of capsaicin-induced cell death because bonkrekic acid and cyclosporin A, inhibitors of mitochondrial permeability transition, block this cell death. These results imply that capsaicin induces mitochondrial dysfunction in VR1-expressing cells, leading to apoptotic cell death, which is a well-known neurotoxic effect of capsaicin.

Animals↗
PubMed2003

Calcium-activated cationic channel in rat sensory neurons.

Ion channels in sensory neurons are molecular sensors that detect external stimuli and transduce them to neuronal signals. Although Ca2+-activated nonselective cation (CAN) channels were found in many cell types, CAN channels in mammalian sensory neurons are not yet identified. In the present study, we describe an ion channel that is activated by intracellular Ca2+ in cultured rat sensory neurons. Half-maximal concentration of Ca2+ in activating the CAN channel was approximately 780 micro m. The current-voltage relationship of this channel was linear with a unit conductance of 28.8 +/- 0.4 pS at -60 mV in symmetrical 140 mm Na+ solution. The CAN channel was permeable to monovalent cations such as Na+, K+, Cs+, and Li+, but poorly permeable to Ca2+. The CAN channel in mammalian sensory neurons was reversibly blocked by intracellular adenine nucleotides, such as ATP, ADP, and AMP. Interestingly, single-channel currents activated by Ca2+ were blocked by fenamates, such as flufenamic acid, a class of nonsteroidal anti-inflammatory drugs. Thus, these results suggest that CAN channels in mammalian sensory neurons would participate in modulating nociceptive neural transmission in response to ever-changing intracellular Ca2+ in the local microenvironment.

Adenine Nucleotides↗
PubMed2002

Agonist recognition sites in the cytosolic tails of vanilloid receptor 1.

Vanilloid receptor 1 (VR1), a ligand-gated ion channel activated by vanilloids, acid, and heat, is a molecular detector that integrates multiple modes of pain. Although the function and the biophysical properties of the channel are now known, the regions of VR1 that recognize ligands are largely unknown. By the stepwise deletion of VR1 and by chimera construction using its capsaicin-insensitive homologue, VRL1, we localized key amino acids, Arg-114 and Glu-761, in the N- and C-cytosolic tails, respectively, that determine ligand binding. Point mutations of the two key residues resulted in a loss of sensitivity to capsaicin and a concomitant loss of specific binding to [(3)H]resiniferatoxin, a potent vanilloid. Furthermore, changes in the charges of the two amino acids blocked capsaicin-sensitive currents and ligand binding without affecting current responses to heat. Thus, these two regions in the cytoplasmic tails of VR1 provide structural elements for its hydrophilic interaction with vanilloids and might constitute a long-suspected binding pocket.

Animals↗
PubMed2002

Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia.

The capsaicin-sensitive vanilloid receptor (VR1) was recently shown to play an important role in inflammatory pain (hyperalgesia), but the underlying mechanism is unknown. We hypothesized that pain-producing inflammatory mediators activate capsaicin receptors by inducing the production of fatty acid agonists of VR1. This study demonstrates that bradykinin, acting at B2 bradykinin receptors, excites sensory nerve endings by activating capsaicin receptors via production of 12-lipoxygenase metabolites of arachidonic acid. This finding identifies a mechanism that might be targeted in the development of new therapeutic strategies for the treatment of inflammatory pain.

Animals↗
PubMed2002

Mechanosensitive ion channels in cultured sensory neurons of neonatal rats.

Mechanosensitive (MS) ion channels are present in a variety of cells. However, very little is known about the ion channels that account for mechanical sensitivity in sensory neurons. We identified the two most frequently encountered but distinct types of MS channels in 1390 of 2962 membrane patches tested in cultured dorsal root ganglion neurons. The two MS channels exhibited different thresholds, thus named as low-threshold (LT) and high-threshold (HT) MS channels, and sensitivity to pressure. The two channels retained different single-channel conductances and current-voltage relationships: LT and HT channels elicited large- and small-channel conductance with outwardly rectifying and linear I-V relationships, respectively. Both LT and HT MS channels were permeable to monovalent cations and Ca2+ and were blocked by gadolinium, a blocker of MS channels. Colchicine and cytochalasin D markedly reduced the activities of the two MS channels, indicating that cytoskeletal elements support the mechanosensitivity. Both types of MS channels were found primarily in small sensory neurons with diameters of <30 microm. Furthermore, HT MS channels were sensitized by a well known inducer of mechanical hyperalgesia, prostaglandin E2, via the protein kinase A pathway. We identified two distinct types of MS channels in sensory neurons that probably give rise to the observed MS whole-cell currents and transduce mechanical stimuli to neural signals involved in somatosensation, including pain.

Amiloride↗
PubMed2002

Hot channels in airways: pharmacology of the vanilloid receptor.

Airway hyperresponsiveness of the tracheobronchial path is recognized as the critical feature of bronchial asthma. Sensory nerves in the airway are implicated strongly in this hyperresponsiveness. The vanilloid VR1 receptor, a cloned capsaicin receptor and a nociceptor-specific cation channel, is known to detect and transduce various harmful stimuli to electrical signals. Recent findings suggest that bradykinin can activate VR1 through generation of lipoxygenase products and that protein kinase C and phospholipase C mediate the sensitization of VR1 by many key inflammatory mediators. Such findings will lead to a better understanding of the enigmatic etiology of asthma.

Animals↗