A Collision Coupling Model Governs the Activation of Neuronal GIRK1/2 Channels by Muscarinic-2 Receptors.

The G protein-activated Inwardly Rectifying K-channel (GIRK) modulates heart rate and neuronal excitability. Following G-Protein Coupled Receptor (GPCR)-mediated activation of heterotrimeric G proteins (Gαβγ), opening of the channel is obtained by direct binding of Gβγ subunits. Interestingly, GIRKs are solely activated by Gβγ subunits released from Gα-coupled GPCRs, despite the fact that all receptor types, for instance Gα-coupled, are also able to provide Gβγ subunits.

The coupling of the M2 muscarinic receptor to its G protein is voltage dependent.

G protein coupled receptors (GPCRs) participate in the majority of signal transduction processes in the body. Specifically, the binding of an external agonist promotes coupling of the GPCR to its G protein and this, in turn, induces downstream signaling. Recently, it was shown that agonist binding to the M2 muscarinic receptor (M2R) and to other GPCRs is voltage dependent.

A Novel Voltage Sensor in the Orthosteric Binding Site of the M2 Muscarinic Receptor.

G protein-coupled receptors (GPCRs) mediate many signal transduction processes in the body. The discovery that these receptors are voltage-sensitive has changed our understanding of their behavior. The M2 muscarinic acetylcholine receptor (M2R) was found to exhibit depolarization-induced charge movement-associated currents, implying that this prototypical GPCR possesses a voltage sensor.

Voltage affects the dissociation rate constant of the m2 muscarinic receptor.

G-protein coupled receptors (GPCRs) comprise the largest protein family and mediate the vast majority of signal transduction processes in the body. Until recently GPCRs were not considered to be voltage dependent. Newly it was shown for several GPCRs that the first step in GPCR activation, the binding of agonist to the receptor, is voltage sensitive: Voltage shifts the receptor between two states that differ in their binding affinity.

Selecting the particle size distribution for drugs with low water solubility - mathematical model.

Purpose: To introduce guidelines in selecting the particle size distribution (n(0), cm(-1)) that will guarantee optimal oral absorption for drugs with low solubility.

Methods: Unlike other multi-compartmental models the gastrointestinal tract is modeled as a continuous tube with spatially varying properties. The transport through the intestinal lumen is described using the dispersion model.

Depolarization induces a conformational change in the binding site region of the M2 muscarinic receptor.

G protein-coupled receptors play a central role in signal transduction and were only known to be activated by agonists. Recently it has been shown that membrane potential also affects the activity of G protein-coupled receptors. For the M(2) muscarinic receptor, it was further shown that depolarization induces charge movement.

A novel fast mechanism for GPCR-mediated signal transduction--control of neurotransmitter release.

Reliable neuronal communication depends on accurate temporal correlation between the action potential and neurotransmitter release. Although a requirement for Ca(2+) in neurotransmitter release is amply documented, recent studies have shown that voltage-sensitive G protein-coupled receptors (GPCRs) are also involved in this process. However, how slow-acting GPCRs control fast neurotransmitter release is an unsolved question.

Control of neurotransmitter release: From Ca2+ to voltage dependent G-protein coupled receptors.

This review discusses two theories that try to explain mechanisms of control of neurotransmitter release in fast synapses: the Ca(2+) hypothesis and the Ca(2+) voltage hypothesis. The review summarizes experimental results that are incompatible with predictions from the Ca(2+) hypothesis and concludes that Ca(2+) is involved in the control of the amount of release but not in the control of the time course of evoked release, i.e.

New mechanism for voltage induced charge movement revealed in GPCRs--theory and experiments.

Depolarization induced charge movement associated currents, analogous to gating currents in channels, were recently demonstrated in G-protein coupled receptors (GPCRs), and were found to affect the receptor's Agonist binding Affinity, hence denoted AA-currents. Here we study, employing a combined theoretical-experimental approach, the properties of the AA-currents using the m2-muscarinic receptor (m2R) as a case study. We found that the AA-currents are characterized by a "bump", a distinct rise followed by a slow decline, which appears both in the On and the Off responses.

Molecular mechanisms that control initiation and termination of physiological depolarization-evoked transmitter release.

Ca(2+) is essential for physiological depolarization-evoked synchronous neurotransmitter release. But, whether Ca(2+) influx or another factor controls release initiation is still under debate. The time course of ACh release is controlled by a presynaptic inhibitory G protein-coupled autoreceptor (GPCR), whose agonist-binding affinity is voltage-sensitive.

The chemical synapse goes electric: Ca2+- and voltage-sensitive GPCRs control neurotransmitter release.

It is widely believed that the initiation of transmitter release in fast synapses is triggered by rapid Ca2+ entry and that the termination of release is governed by removal of Ca2+ from below the release sites. We argue that, although Ca2+ is essential for release, fast-entry kinetics render Ca2+ incapable of being the limiting factor for the initiation of release, and the relatively slow removal of Ca2+ cannot be the limiting factor for the termination of release. We suggest, and provide supporting evidence for, a novel general mechanism for control of fast transmitter release (in the range of milliseconds) from nerve terminals.

Movement of 'gating charge' is coupled to ligand binding in a G-protein-coupled receptor.

Activation by agonist binding of G-protein-coupled receptors (GPCRs) controls most signal transduction processes. Although these receptors span the cell membrane, they are not considered to be voltage sensitive. Recently it was shown that both the activity of GPCRs and their affinity towards agonists are regulated by membrane potential.

On the feedback between theory and experiment in elucidating the molecular mechanisms underlying neurotransmitter release.

This review describes the development of the molecular level Ca(2+)-voltage hypothesis. Theoretical considerations and feedback between theory and experiments played a key role in its development. The theory, backed by experiments, states that at fast synapses, membrane potential by means of presynaptic inhibitory autoreceptors controls initiation and termination of neurotransmitter release.

The metabotropic glutamate G-protein-coupled receptors mGluR3 and mGluR1a are voltage-sensitive.

G-protein-coupled receptors play a key role in signal transduction processes. Despite G-protein-coupled receptors being transmembrane proteins, the notion that they exhibit voltage sensitivity is rather novel. Here we examine whether two metabotropic glutamate receptors, mGluR3 and mGluR1a, both involved in fundamental physiological processes, exhibit, by themselves, voltage sensitivity.

Release of neurotransmitter induced by Ca2+-uncaging: reexamination of the ca-voltage hypothesis for release.

The primacy of Ca2+ in controlling the amount of released neurotransmitter is well established. However, it is not yet clear what controls the time-course (initiation and termination) of release. Various experiments indicated that the time-course is controlled by membrane potential per se.

Mathematical modeling and optimization of drug delivery from intratumorally injected microspheres.

Purpose: Paclitaxel is a highly promising phase-sensitive antitumor drug that could conceivably be improved by extended lower dosing as opposed to intermittent higher dosing. Although intratumoral delivery of paclitaxel to the whole tumor at different loads and rates has already been achieved, determining an optimal release mode of paclitaxel for tumor eradication remains difficult. This study set out to rationally design such an optimal microsphere release mode based on mathematical modeling.

The M2 muscarinic G-protein-coupled receptor is voltage-sensitive.

G-protein coupled receptors are not considered to exhibit voltage sensitivity. Here, using Xenopus oocytes, we show that the M2 muscarinic receptor (m2R) is voltage-sensitive. The m2R-mediated potassium channel (GIRK) currents were used to assay the activity of m2R.

Can the Ca2+ hypothesis and the Ca2+-voltage hypothesis for neurotransmitter release be reconciled?

It is well established that Ca2+ plays a key role in promoting the physiological depolarization-induced release (DIR) of neurotransmitters from nerve terminals (Ca2+ hypothesis). Yet, evidence has accumulated for the Ca2+-voltage hypothesis, which states that not only is Ca2+ required, but membrane potential as such also plays a pivotal role in promoting DIR. An essential aspect of the Ca2+-voltage hypothesis is that it is depolarization that is responsible for the initiation of release.

Reaction diffusion model of the enzymatic erosion of insoluble fibrillar matrices.

Predicting the time course of in vivo biodegradation is a key issue in the design of an increasing number of biomedical applications such as sutures, tissue analogs and drug-delivery devices. The design of such biodegradable devices is hampered by the absence of quantitative models for the enzymatic erosion of solid protein matrices. In this work, we derive and simulate a reaction diffusion model for the enzymatic erosion of fibrillar gels that successfully reproduces the main qualitative features of this process.

Ca2+-independent feedback inhibition of acetylcholine release in frog neuromuscular junction.

The effect of membrane potential on feedback inhibition of acetylcholine (ACh) release was studied using the frog neuromuscular junction. It was found that membrane potential affects the functional affinity (K(i)) of the presynaptic M2 muscarinic receptor. The K(i) for muscarine shifts from approximately 0.