Effector Contributions to Gβγ-mediated Signaling as Revealed by Muscarinic Potassium Channel Gating

Ivanova-Nikolova, Tatyana T.; Breitwieser, Gerda E.

doi:10.1085/jgp.109.2.245

Cited by 37 publications

(47 citation statements)

References 36 publications

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“…Several consistent possibilities have been suggested to explain modal gating in other channels, such as phosphorylation [171,213], binding of accessory proteins [47,89,90,107,115,213,223], ligand-independent conformational changes [24,115], or alterations at the channel pore [34]. Our model demonstrates that, in general, these mechanisms can act locally, by influencing even a single subunit, and that this is sufficient to generate the many distinct channel states assumed in whole-channel models.…”

Section: 4a) If Openingsupporting

confidence: 66%

“…Four gating modes of GIRK1/4 channels in atrial myocytes were posited to arise directly from the independent binding of up to four G protein G βγ subunits to the tetrameric channel [89,90]. At much longer timescales of tens of seconds, GIRK1/4 channels expressed in Xenopus oocytes switch between periods of high and low activity even at saturating G βγ [213].…”

Section: Application To Other Ion Channelsmentioning

confidence: 99%

“…However, these are precisely the channel behaviors predicted by the modal gating motif, implemented without the constraint on ligand occupancy we assumed for the IP 3 R. The liganddependent activation step in the motif accounts for the faster G βγ -dependent switching observed by refs. [89,90], whereas the slow sequestration incorporates the G βγ -independent regulation observed by ref. [213].…”

Section: Application To Other Ion Channelsmentioning

confidence: 99%

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Noise and sensitivity in cell signalling

Bicknell¹

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The ability of cells to receive and process chemical information is fundamental to the function of biological systems. Cell responses to salient chemical cues are characteristically reliable and precise, a striking example being the guidance of axons to their targets during brain development. However, chemical signalling pathways are subject to multiple sources of unavoidable noise, due to the random nature of molecular motion and interactions. This suggests that cellular systems may be optimised for transduction of noisy signals, which provides a guiding principle for understanding cell function at a biophysical level. In pursuit of this idea, we study three model problems, motivated by sensing and signalling in axon guidance. Our approach is to construct mathematical models, and through analysis and simulation, extract general principles and hypotheses about the quantitative nature of biological noise and mechanisms for sensitive chemosensation.First, we quantify the physical limits of chemosensation imposed by the random thermal motion of the molecules that need to be counted. In particular, we show how this depends on the dimension and spatial extent of the domain of diffusion. Although recurrent diffusion in 1d and 2d is detrimental to measurement precision, we find these effects are suppressed when sensing is performed within a confined space. Second, we study the stochastic behaviour of the inositol 1,4,5-trisphosphate receptor ion channel, which couples receptor activity at the membrane to the downstream calcium response that regulates axon growth and turning. By modelling the basic biophysical events that control ion channel opening, we introduce a new principle for understanding the origin of the multiple gating modes observed in single channel recordings. Third, we examine the finely-tuned response of dorsal root ganglia neurons to very shallow neurotrophin gradients. We show how paracrine signalling within the ganglion could explain this extreme sensitivity, as well as the currently unexplained biphasic dose response of many axon growth and guidance cues.Overall, this thesis gives new quantitative insights into chemical signalling in biological systems, across multiple stages of processing and spatial scales. Our models make testable predictions to motivate new experiments, and provide a strong foundation for further theoretical and computational study in both axon guidance and broader domains of biophysics.iii

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Section: 4a) If Openingsupporting

confidence: 66%

Section: Application To Other Ion Channelsmentioning

confidence: 99%

Section: Application To Other Ion Channelsmentioning

confidence: 99%

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Noise and sensitivity in cell signalling

Bicknell¹

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show abstract

“…Four gating modes of GIRK1/4 channels in atrial myocytes were posited to arise directly from the independent binding of up to four G-protein G βγ subunits to the tetrameric channel (14,15). At much longer timescales of tens of seconds, GIRK1/4 channels expressed in Xenopus oocytes switch between periods of high and low activity even at saturating G βγ (17).…”

Section: Discussionmentioning

confidence: 99%

“…A detailed understanding of this important feature of IP 3 R behavior is therefore crucial for unraveling the complexity of Ca 2+ signaling and its role in cell function and disease. Modal gating has been observed in the kinetics of many other ion channels, such as K + (13)(14)(15)(16)(17)(18), Cl − (19), glutamate receptors (20,21), plasma membrane Ca 2+ (22)(23)(24), and ryanodine receptor Ca 2+ (25,26). However, the underlying biophysical basis of modal gating in the IP 3 R and most other channels remains unknown.…”

mentioning

confidence: 99%

Emergence of ion channel modal gating from independent subunit kinetics

Bicknell

Goodhill

2016

Proc. Natl. Acad. Sci. U.S.A.

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Many ion channels exhibit a slow stochastic switching between distinct modes of gating activity. This feature of channel behavior has pronounced implications for the dynamics of ionic currents and the signaling pathways that they regulate. A canonical example is the inositol 1,4,5-trisphosphate receptor (IP3R) channel, whose regulation of intracellular Ca2+ concentration is essential for numerous cellular processes. However, the underlying biophysical mechanisms that give rise to modal gating in this and most other channels remain unknown. Although ion channels are composed of protein subunits, previous mathematical models of modal gating are coarse grained at the level of whole-channel states, limiting further dialogue between theory and experiment. Here we propose an origin for modal gating, by modeling the kinetics of ligand binding and conformational change in the IP3R at the subunit level. We find good agreement with experimental data over a wide range of ligand concentrations, accounting for equilibrium channel properties, transient responses to changing ligand conditions, and modal gating statistics. We show how this can be understood within a simple analytical framework and confirm our results with stochastic simulations. The model assumes that channel subunits are independent, demonstrating that cooperative binding or concerted conformational changes are not required for modal gating. Moreover, the model embodies a generally applicable principle: If a timescale separation exists in the kinetics of individual subunits, then modal gating can arise as an emergent property of channel behavior.

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α7 nicotinic acetylcholine receptors induce long‐term synaptic enhancement in the dorsal but not ventral hippocampus

Tsotsokou,

Kouri,

Papatheodoropoulos

2024

Synapse

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Agents that positively modulate the activity of α7nAChRs are used as cognitive enhancers and for the treatment of hippocampus‐dependent functional decline. However, it is not known whether the expression and the effects of α7nAChRs apply to the entire longitudinal axis of the hippocampus equally. Given that cholinergic system‐involving hippocampal functions are not equally distributed along the hippocampus, we comparatively examined the expression and the effects of α7nAChRs on excitatory synaptic transmission between the dorsal and the ventral hippocampal slices from adult rats. We found that α7nAChRs are equally expressed in the CA1 field of the two segments of the hippocampus. However, activation of α7nAChRs by their highly selective agonist PNU 282987 induced a gradually developing increase in field excitatory postsynaptic potential only in the dorsal hippocampus. This long‐term potentiation was not reversed upon application of nonselective nicotinic receptor antagonist mecamylamine, but the induction of potentiation was prevented by prior blockade of α7nAChRs by their antagonist MG 624. In contrast to the long‐term synaptic plasticity, we found that α7nAChRs did not modulate short‐term synaptic plasticity in either the dorsal or the ventral hippocampus. These results may have implications for the role that α7nAChRs play in specifically modulating functions that depend on the normal function of the dorsal hippocampus. We propose that hippocampal functions that rely on a direct α7 nAChR‐mediated persistent enhancement of glutamatergic synaptic transmission are preferably supported by dorsal but not ventral hippocampal synapses.

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Effector Contributions to Gβγ-mediated Signaling as Revealed by Muscarinic Potassium Channel Gating

Cited by 37 publications

References 36 publications

Noise and sensitivity in cell signalling

Noise and sensitivity in cell signalling

Emergence of ion channel modal gating from independent subunit kinetics

α7 nicotinic acetylcholine receptors induce long‐term synaptic enhancement in the dorsal but not ventral hippocampus

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