Real-Time Spectroscopic Analysis of Ligand-Receptor Dynamics

Sklar, L A

doi:10.1146/annurev.bb.16.060187.002403

Cited by 43 publications

(16 citation statements)

References 37 publications

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“…The second assumption is that the rates of activators binding to channels are much faster than the time scales for the activators to stimulate the channels. This assumption is in agreement with the general experimental observation that ligand-receptor binding is at the level of a microsecond (Sktar, 1987 ) and our recent observation that, in the presence of ztz240, the closing of KCNQ2 takes approximately 10 s (Gao et al, 2010 ). These two assumptions enable us to apply equilibrium thermodynamic tools to develop the activation model of ztz240 binding to KCNQ2.…”

Section: Methodssupporting

confidence: 91%

A Statistical Thermodynamic Model for Ligands Interacting With Ion Channels: Theoretical Model and Experimental Validation of the KCNQ2 Channel

Bai

et al. 2018

Front. Pharmacol.

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Ion channels are important therapeutic targets, and their pharmacology is becoming increasingly important. However, knowledge of the mechanism of interaction of the activators and ion channels is still limited due to the complexity of the mechanisms. A statistical thermodynamic model has been developed in this study to characterize the cooperative binding of activators to ion channels. By fitting experimental concentration-response data, the model gives eight parameters for revealing the mechanism of an activator potentiating an ion channel, i.e., the binding affinity (KA), the binding cooperative coefficients for two to four activator molecules interacting with one channel (γ, μ, and ν), and the channel conductance coefficients for four activator binding configurations of the channel (a, b, c, and d). Values for the model parameters and the mechanism underlying the interaction of ztz240, a proven KCNQ2 activator, with the wild-type channel have been obtained and revealed by fitting the concentration-response data of this activator potentiating the outward current amplitudes of KCNQ2. With these parameters, our model predicted an unexpected bi-sigmoid concentration-response curve of ztz240 activation of the WT-F137A mutant heteromeric channel that was in good agreement with the experimental data determined in parallel in this study, lending credence to the assumptions on which the model is based and to the model itself. Our model can provide a better fit to the measured data than the Hill equation and estimates the binding affinity, as well as the cooperative coefficients for the binding of activators and conductance coefficients for binding states, which validates its use in studying ligand-channel interaction mechanisms.

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Section: Methodssupporting

confidence: 91%

A Statistical Thermodynamic Model for Ligands Interacting With Ion Channels: Theoretical Model and Experimental Validation of the KCNQ2 Channel

Bai

et al. 2018

Front. Pharmacol.

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“…Dictyostelium chemoattractant receptors do not have such high affinities (Janssens and Van Haastert, 1987), and increases in bound ligand due to the affinity are unlikely to occur in these cells. On the contrary, neutrophils do have high-affinity receptors for chemoattractants (Sklar, 1987), and these affinity properties have been used for detailed comparisons of ligand-receptor kinetics with downstream signaling pathways in neutrophils (Sklar, 1987), although not in studies involving spatial gradients of fluorescent ligands.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Distribution during Chemotactic Responses

Bailly¹,

Wyckoff²,

Bouzahzah

et al. 2000

MBoC

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To determine the distribution of the epidermal growth factor (EGF) receptor (EGFR) on the surface of cells responding to EGF as a chemoattractant, an EGFR-green fluorescent protein chimera was expressed in the MTLn3 mammary carcinoma cell line. The chimera was functional and easily visualized on the cell surface. In contrast to other studies indicating that the EGFR might be localized to certain regions of the plasma membrane, we found that the chimera is homogeneously distributed on the plasma membrane and becomes most concentrated in vesicles after endocytosis. In spatial gradients of EGF, endocytosed receptor accumulates on the upgradient side of the cell. Visualization of the binding of fluorescent EGF to cells reveals that the affinity properties of the receptor, together with its expression level on cells, can provide an initial amplification step in spatial gradient sensing.

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“…First, at small values of Ta, (0) increases *For a diffusion-limited ligand-receptor interaction (51), where the lateral translational diffusion coefficient (D) of the receptor is typically between 10-"-10-8 cm2/s (52). tSmaller values are seen when the receptor-ligand interaction is not diffusion limited (53). with Ta.…”

Section: Attachmentmentioning

confidence: 99%

Receptor-mediated cell attachment and detachment kinetics. I. Probabilistic model and analysis

Cozens-Roberts

Lauffenburger

Quinn

1990

Biophysical Journal

160

139

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The kinetics of receptor-mediated cell adhesion to a ligand-coated surface play a key role in many physiological and biotechnology-related processes. We present a probabilistic model of receptor-ligand bond formation between a cell and surface to describe the probability of adhesion in a fluid shear field. Our model extends the deterministic model of Hammer and Lauffenburger (Hammer, D.A., and D.A. Lauffenburger. 1987. Biophys. J. 52:475-487) to a probabilistic framework, in which we calculate the probability that a certain number of bonds between a cell and surface exists at any given time. The probabilistic framework is used to account for deviations from ideal, deterministic behavior, inherent in chemical reactions involving relatively small numbers of reacting molecules. Two situations are investigated: first, cell attachment in the absence of fluid stress; and, second, cell detachment in the presence of fluid stress. In the attachment case, we examine the expected variance in bond formation as a function of attachment time; this also provides an initial condition for the detachment case. Focusing then on detachment, we predict transient behavior as a function of key system parameters, such as the distractive fluid force, the receptor-ligand bond affinity and rate constants, and the receptor and ligand densities. We compare the predictions of the probabilistic model with those of a deterministic model, and show how a deterministic approach can yield some inaccurate results; e.g., it cannot account for temporally continuous cell attach mentor detachment, it can underestimate the time needed for cell attachment, it can overestimate the time required for cell detachment for a given level of force, and it can overestimate the force necessary for cell detachment.

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Real-Time Spectroscopic Analysis of Ligand-Receptor Dynamics

Cited by 43 publications

References 37 publications

A Statistical Thermodynamic Model for Ligands Interacting With Ion Channels: Theoretical Model and Experimental Validation of the KCNQ2 Channel

A Statistical Thermodynamic Model for Ligands Interacting With Ion Channels: Theoretical Model and Experimental Validation of the KCNQ2 Channel

Epidermal Growth Factor Receptor Distribution during Chemotactic Responses

Receptor-mediated cell attachment and detachment kinetics. I. Probabilistic model and analysis

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