Structural determinants at the M2 muscarinic receptor modulate the RGS4-GIRK response to pilocarpine by impairment of the receptor voltage sensitivity.

Membrane potential controls the response of the M2 muscarinic receptor to its ligands. Membrane hyperpolarization increases response to the full agonist acetylcholine (ACh) while decreasing response to the partial agonist pilocarpine. We previously have demonstrated that the regulator of G-protein signaling (RGS) 4 protein discriminates between the voltage-dependent responses of ACh and pilocarpine; however, the underlying mechanism remains unclear. Here we show that RGS4 is involved in the voltage-dependent behavior of the M2 muscarinic receptor-mediated signaling in response to pilocarpine. Additionally we revealed structural determinants on the M2 muscarinic receptor underlying the voltage-dependent response. By electrophysiological recording in Xenopus oocytes expressing M2 muscarinic receptor and G-protein-gated inwardly rectifying K+ channels, we quantified voltage-dependent desensitization of pilocarpine-induced current in the presence or absence of RGS4. Hyperpolarization-induced desensitization of the current required for RGS4, also depended on pilocarpine concentration. Mutations of charged residues in the aspartic acid-arginine-tyrosine motif of the M2 muscarinic receptor, but not intracellular loop 3, significantly impaired the voltage-dependence of RGS4 function. Thus, our results demonstrated that voltage-dependence of RGS4 modulation is derived from the M2 muscarinic receptor. These results provide novel insights into how membrane potential impacts G-protein signaling by modulating GPCR communication with downstream effectors

RGS4 regulates partial agonism of the M2 muscarinic receptor-activated K+ currents.

Partial agonists are used clinically to avoid overstimulation of receptor-mediated signalling, as they produce a submaximal response even at 100% receptor occupancy. The submaximal efficacy of partial agonists is due to conformational change of the agonist-receptor complex, which reduces effector activation. In addition to signalling activators, several regulators help control intracellular signal transductions. However, it remains unclear whether these signalling regulators contribute to partial agonism. Here we show that regulator of G-protein signalling (RGS) 4 is a determinant for partial agonism of the M2 muscarinic receptor (M2R). In rat atrial myocytes, pilocarpine evoked smaller G-protein-gated K(+) inwardly rectifying (KG) currents than those evoked by ACh. In a Xenopus oocyte expression system, pilocarpine acted as a partial agonist in the presence of RGS4 as it did in atrial myocytes, while it acted like a full agonist in the absence of RGS4. Functional couplings within the agonist-receptor complex/G-protein/RGS4 system controlled the efficacy of pilocarpine relative to ACh. The pilocarpine-M2R complex suppressed G-protein-mediated activation of KG currents via RGS4. Our results demonstrate that partial agonism of M2R is regulated by the RGS4-mediated inhibition of G-protein signalling. This finding helps us to understand the molecular components and mechanism underlying the partial agonism of M2R-mediated physiological responses

Highly nonclassical photon statistics in parametric down conversion

We use photon counters to obtain the joint photon counting statistics from twin-beam non-degenerate parametric down conversion, and we demonstrate directly, and with no auxiliary assumptions, that these twin beams are nonclassical

Facilitation of I Kr current by some hERG channel blockers suppresses early afterdepolarizations.

Drug-induced block of the cardiac rapid delayed rectifying potassium current (I Kr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of I Kr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive I Kr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing I Kr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias

Approximate quantum error correction can lead to better codes

We present relaxed criteria for quantum error correction which are useful when the specific dominant noise process is known. These criteria have no classical analogue. As an example, we provide a four-bit code which corrects for a single amplitude damping error. This code violates the usual Hamming bound calculated for a Pauli description of the error process, and does not fit into the GF(4) classification.Comment: 7 pages, 2 figures, submitted to Phys. Rev.

Quantum simulation of spin ordering with nuclear spins in a solid state lattice

An experiment demonstrating the quantum simulation of a spin-lattice Hamiltonian is proposed. Dipolar interactions between nuclear spins in a solid state lattice can be modulated by rapid radio-frequency pulses. In this way, the effective Hamiltonian of the system can be brought to the form of an antiferromagnetic Heisenberg model with long range interactions. Using a semiconducting material with strong optical properties such as InP, cooling of nuclear spins could be achieved by means of optical pumping. An additional cooling stage is provided by adiabatic demagnetization in the rotating frame (ADRF) down to a nuclear spin temperature at which we expect a phase transition from a paramagnetic to antiferromagnetic phase. This phase transition could be observed by probing the magnetic susceptibility of the spin-lattice. Our calculations suggest that employing current optical pumping technology, observation of this phase transition is within experimental reach.Comment: 11 pages, 3 figues; Published versio

Quantum Bit Regeneration

Decoherence and loss will limit the practicality of quantum cryptography and computing unless successful error correction techniques are developed. To this end, we have discovered a new scheme for perfectly detecting and rejecting the error caused by loss (amplitude damping to a reservoir at T=0), based on using a dual-rail representation of a quantum bit. This is possible because (1) balanced loss does not perform a ``which-path'' measurement in an interferometer, and (2) balanced quantum nondemolition measurement of the ``total'' photon number can be used to detect loss-induced quantum jumps without disturbing the quantum coherence essential to the quantum bit. Our results are immediately applicable to optical quantum computers using single photonics devices.Comment: 4 pages, postscript only, figures available at http://feynman.stanford.edu/qcom

Efficient implementation of selective recoupling in heteronuclear spin systems using Hadamard matrices

We present an efficient scheme which couples any designated pair of spins in heteronuclear spin systems. The scheme is based on the existence of Hadamard matrices. For a system of $n$ spins with pairwise coupling, the scheme concatenates $cn$ intervals of system evolution and uses at most $c n^2$ pulses where $c \approx 1$. Our results demonstrate that, in many systems, selective recoupling is possible with linear overhead, contrary to common speculation that exponential effort is always required.Comment: 7 pages, 4 figures, mypsfig2, revtex, submitted April 27, 199

A molecular dynamics simulation of polymer crystallization from oriented amorphous state

Molecular process of crystallization from an oriented amorphous state was reproduced by molecular dynamics simulation for a realistic polyethylene model. Initial oriented amorphous state was obtained by uniaxial drawing an isotropic glassy state at 100 K. By the temperature jump from 100 K to 330 K, there occurred the crystallization into the fiber structure, during the process of which we observed the developments of various order parameters. The real space image and its Fourier transform revealed that a hexagonally ordered domain was initially formed, and then highly ordered crystalline state with stacked lamellae developed after further adjustment of the relative heights of the chains along their axes.Comment: 4 pages, 3 figure