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Closed State (closed + state)
Selected AbstractsGating of the expressed T-type Cav3.1 calcium channels is modulated by Ca2+ACTA PHYSIOLOGICA, Issue 4 2006L. Lacinová Abstract Aim:, We have investigated the influence of Ca2+ ions on the basic biophysical properties of T-type calcium channels. Methods:, The Cav3.1 calcium channel was transiently expressed in HEK 293 cells. Current was measured using the whole cell patch clamp technique. Ca2+ or Na+ ions were used as charge carriers. The intracellular Ca2+ was either decreased by the addition of 10 mm ethyleneglycoltetraacetic acid (EGTA) or increased by the addition of 200 ,m Ca2+ into the non-buffered intracellular solution. Various combinations of extra- and intracellular solutions yielded high, intermediate or low intracellular Ca2+ levels. Results:, The amplitude of the calcium current was independent of intracellular Ca2+ concentrations. High levels of intracellular Ca2+ accelerated significantly both the inactivation and the activation time constants of the current. The replacement of extracellular Ca2+ by Na+ as charge carrier did not affect the absolute value of the activation and inactivation time constants, but significantly enhanced the slope factor of the voltage dependence of the inactivation time constant. Slope factors of voltage dependencies of channel activation and inactivation were significantly enhanced. The recovery from inactivation was faster when Ca2+ was a charge carrier. The number of available channels saturated for membrane voltages more negative than ,100 mV for the Ca2+ current, but did not reach steady state even at ,150 mV for the Na+ current. Conclusions:, Ca2+ ions facilitate transitions of Cav3.1 channel from open into closed and inactivated states as well as backwards transition from inactivated into closed state, possibly by interacting with its voltage sensor. [source] G-protein coupled receptors: SAR analyses of neurotransmitters and antagonistsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2004C. L. Kuo MS Summary Background:, From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (, - and , -), dopaminergic, serotoninergic (5-HT1,5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. Objective:, The aim of the present study is to examine the structure,activity relationships of agents acting on G-protein coupled receptors. Method:, Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians' desk reference; M.J. O'Neil (2001) The Merck index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), Elumo (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), Ehomo (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (Hb) (donors and receptors), were chosen as molecular descriptors for SAR analyses. Results:, The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and , as independent variables. Conclusion:, It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors. [source] Polymethylene tetraamine backbone as template for the development of biologically active polyaminesMEDICINAL RESEARCH REVIEWS, Issue 2 2003Carlo Melchiorre Abstract The concept that polyamines may represent a universal template in the receptor recognition process is embodied in the design of ligands for different biological targets. As a matter of fact, the insertion of different pharmacophores onto the polymethylene tetraamine backbone can tune both affinity and selectivity for any given receptor. The application of this approach provided a prospect of modifying benextramine (1) structure to achieve specific recognition of muscarinic receptors that led to the discovery of methoctramine (2), which is widely used as a pharmacological tool for muscarinic receptor characterization. In turn, appropriate structural modifications performed on the structure of methoctramine led to the discovery of new polyamines endowed with high affinity and selectivity for (a) muscarinic receptor subtypes, (b) Gi proteins, and (c) muscle-type nicotinic receptors. Thus, polyamines tripitramine (9) and spirotramine (33), among others, were designed, which were shown to be highly selective for muscarinic M2 and M1 receptors, respectively. Several polyamines have been discovered, which inhibit noncompetitively a closed state of the nicotinic receptor. These ligands, such as 66, resulted in important tools for elucidating the mode and site of interaction of polyamines with the ion channel. It was discovered that reducing the flexibility of the diaminohexane spacer of methoctramine led to polyamines, such as 70, which are endowed with a biological profile significantly different from that of the prototype. Most likely, tetraamine (70) is a potent activator of Gi proteins. Finally, the universal template approach formed the basis for modifying benextramine (1) structure to the design of ligands, which display affinity for acetylcholinesterase and muscarinic M2 receptors. Thus, these polyamines, such as caproctamine (78), could have potential in the investigation of Alzheimer disease. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 2, 200,233, 2003 [source] Internal WWAN antenna for the clamshell mobile phone with various chassis shapesMICROWAVE AND OPTICAL TECHNOLOGY LETTERS, Issue 9 2010Kin-Lu Wong Abstract Stable performances of an internal WWAN antenna applied in the clamshell mobile phone with various chassis shapes are obtained. Six different states including five possible operating states and one closed state (idle condition) of the clamshell mobile phone, wherein the chassis shapes (main ground and upper ground) vary greatly, are studied. The WWAN antenna is mounted at the bottom of the main ground, and there are three connecting positions between the main ground and the upper ground. For each operating states, the upper ground is connected to the main ground at one of the three connecting positions. At each position, a band-stop circuit formed by two parallel LC chip elements is embedded, which is designed to excite a parallel resonance at around 900 MHz and hence leads to very high impedance seen into the upper ground in the 900 MHz band. This greatly decreases the excited surface currents on the upper ground, making the presence of the upper ground to have very small effects on the performances of the WWAN antenna mounted at the bottom of the main ground. At around 1900 MHz, owing to its shorter wavelength, the surface currents on the upper ground excited by the WWAN antenna on the main ground are small. Thus, over both the 900- and 1900-MHz bands, the various orientations of the upper ground to the main ground cause small effects on the WWAN antenna embedded therein. Details of the obtained results are presented. © 2010 Wiley Periodicals, Inc. Microwave Opt Technol Lett 52: 2148,2154, 2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.25413 [source] Pacemaker Reed Switch Behavior in 0.5, 1.5, and 3.0 Tesla Magnetic Resonance Imaging Units: Are Reed Switches Always Closed in Strong Magnetic Fields?PACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 10 2002ROGER LUECHINGER LUECHINGER, R., et al.: Pacemaker Reed Switch Behavior in 0.5, 1.5, and 3.0 Tesla Magnetic Resonance Imaging Units: Are Reed Switches Always Closed in Strong Magnetic Fields? MRI is established as an important diagnostic tool in medicine. However, the presence of a cardiac pacemaker is usually regarded as a contraindication for MRI due to safety reasons. The aim of this study was to investigate the state of a pacemaker reed switch in different orientations and positions in the main magnetic field of 0.5-, 1.5-, and 3.0-T MRI scanners. Reed switches used in current pacemakers and ICDs were tested in 0.5-, 1.5-, and 3.0-T MRI scanners. The closure of isolated reed switches was evaluated for different orientations and positions relative to the main magnetic field. The field strengths to close and open the reed switch and the orientation dependency of the closed state inside the main magnetic field were investigated. The measurements were repeated using two intact pacemakers to evaluate the potential influence of the other magnetic components, like the battery. If the reed switches were oriented parallel to the magnetic fields, they closed at 1.0 ± 0.2 mT and opened at 0.7 ± 0.2 mT. Two different reed switch behaviors were observed at different magnetic field strengths. In low magnetic fields (< 50 mT), the reed switches were closed. However, in high magnetic fields (> 200 mT), the reed switches opened in 50% of all tested orientations. No difference between the three scanners could be demonstrated. The reed switches showed the same behavior whether they were isolated or an integral part of the pacemakers. The reed switch in a pacemaker or an ICD does not necessarily remain closed in strong magnetic fields at 0.5, 1.5, or 3.0 T and the state of the reed switch may not be predictable with certainty in clinical situations. [source] The evolutionarily conserved residue A653 plays a key role in HERG channel closingTHE JOURNAL OF PHYSIOLOGY, Issue 11 2009Svetlana Z. Stepanovic Human ether-a-go-go- related gene (HERG) encodes the rapid, outwardly rectifying K+ current IKr that is critical for repolarization of the cardiac action potential. Congenital HERG mutations or unintended pharmaceutical block of IKr can lead to life-threatening arrhythmias. Here, we assess the functional role of the alanine at position 653 (HERG-A653) that is highly conserved among evolutionarily divergent K+ channels. HERG-A653 is close to the ,glycine hinge' implicated in K+ channel opening, and is flanked by tyrosine 652 and phenylalanine 656, which contribute to the drug binding site. We substituted an array of seven (I, C, S, G, Y, V and T) amino acids at position 653 and expressed individual variants in heterologous systems to assess changes in gating and drug binding. Substitution of A653 resulted in negative shifts of the V1/2 of activation ranging from ,23.6 (A653S) to ,62.5 (A653V) compared to ,11.2 mV for wild-type (WT). Deactivation was also drastically altered: channels with A653I/C substitutions exhibited delayed deactivation in response to test potentials above the activation threshold, while A653S/G/Y/V/T failed to deactivate under those conditions and required hyperpolarization and prolonged holding potentials at ,130 mV. While A653S/G/T/Y variants showed decreased sensitivity to the IKr inhibitor dofetilide, these changes could not be correlated with defects in channel closure. Homology modelling suggests that in the closed state, A653 forms tight contacts with several residues from the neighbouring subunit in the tetramer, playing a key role in S6 helix packing at the narrowest part of the vestibule. Our study suggests that A653 plays an important functional role in the outwardly rectifying gating behaviour of HERG, supporting channel closure at membrane potentials negative to the channel activation threshold. [source] Effect of K+ and Rb+ on the action of verapamil on a voltage-gated K+ channel, hKv1.3: implications for a second open state?BRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2009Z Kuras Background and purpose:, Verapamil blocks current through the voltage-gated K+ channel Kv1.3 in the open and inactivated state of the channel but not the closed state. The binding site for verapamil was proposed to be close to the selectivity filter and the occupancy of the selectivity filter might therefore influence verapamil affinity. Experimental approach:, We investigated the influence of intra- and extracellular K+ and Rb+ on the effect of verapamil by patch-clamp studies, in COS-7 cells transfected with hKv1.3 channels. Key results:, Verapamil affinity was highest in high intracellular K+ concentrations ([K+]i) and lowest in low [Rb+]i, indicating an influence of intracellular cations on verapamil affinity. Experiments with a mutant channel (H399T), exhibiting a strongly reduced C-type inactivated state, demonstrated that part of this changed verapamil affinity in wild-type channels could be caused by altered C-type inactivation. External K+ and Rb+ could influence verapamil affinity by a voltage-dependent entry into the channel thereby modifying the verapamil off-rate and in addition causing a voltage-dependent verapamil off-rate. Conclusions and implications:, Recovery from verapamil block was mainly due to the voltage-dependent closing of channels (state-dependent block), implying a second open state of the channel. This hypothesis was confirmed by the dependency of the tail current time course on duration of the prepulse. We conclude that the wild-type hKv1.3 channel undergoes at least two different conformational changes before finally closing with a low verapamil affinity in one open state and a high verapamil affinity in the other open state. [source] Inhibition of cardiac Na+ current by primaquineBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2002Gerardo Orta-Salazar The electrophysiological effects of the anti-malarial drug primaquine on cardiac Na+ channels were examined in isolated rat ventricular muscle and myocytes. In isolated ventricular muscle, primaquine produced a dose-dependent and reversible depression of dV/dt during the upstroke of the action potential. In ventricular myocytes, primaquine blocked INa+ in a dose-dependent manner, with a Kd of 8.2 ,M. Primaquine (i) increased the time to peak current, (ii) depressed the slow time constant of INa+ inactivation, and (iii) slowed the fast component for recovery of INa+ from inactivation. Primaquine had no effect on: (i) the shape of the I , V curve, (ii) the reversal potential for Na+, (iii) the steady-state inactivation and gNa+ curves, (iv) the fast time constant of inactivation of INa+, and (v) the slow component of recovery from inactivation. Block of INa+ by primaquine was use-dependent. Data obtained using a post-rest stimulation protocol suggested that there was no closed channel block of Na+ channels by primaquine. These results suggest that primaquine blocks cardiac Na+ channels by binding to open channels and unbinding either when channels move between inactivated states or from an inactivated state to a closed state. Cardiotoxicity observed in patients undergoing malaria therapy with aminoquinolines may therefore be due to block of Na+ channels, with subsequent disturbances of impulse conductance and contractility. British Journal of Pharmacology (2002) 135, 751,763; doi:10.1038/sj.bjp.0704460 [source] A DNA Nanomachine Powered by Light IrradiationCHEMBIOCHEM, Issue 5 2008Xingguo Liang Prof. Dr. Light fuel: Photoresponsive nanoscale tweezers fuelled by photons were constructed with azobenzene-modified DNA. The tweezers were photoswitched to the open state with UV light irradiation (,=330,350 nm) and to the closed state with visible light (,=440,460 nm) without the addition of further oligonucleotides as fuel. [source] Silver-Ion-Mediated DNAzyme Switch for the Ultrasensitive and Selective Colorimetric Detection of Aqueous Ag+ and CysteineCHEMISTRY - A EUROPEAN JOURNAL, Issue 14 2009Tao Li Abstract Two states, two applications! An Ag+ -mediated DNAzyme switch has been designed to detect Ag+ and cysteine with high sensitivity and selectivity. In the closed state, Ag+ turns on the switch through the formation of cytosine,Ag+,cytosine base pairs, whereas adding cysteine turns off the open switch because it competitively binds to Ag+. This feature endows the DNAzyme switch with two sensing applications. [source] | ||||||||||||||||