Igor Goychuk

Stochastic resonance as a collective property of ion channel assemblies

By use of a stochastic generalization of the Hodgkin-Huxley model we investigate both the phenomena of stochastic resonance (SR) and coherence resonance (CR) in variable size patches of an excitable cell membrane. Our focus is on the challenge: how internal noise stemming from individual ion channels does affect collective properties of the whole ensemble. We investigate both an unperturbed situation with no applied stimuli and one in which the membrane is stimulated externally by a periodic signal and additional external noise. For the nondriven case, we demonstrate the existence of an optimal size of the membrane patch for which the internal noise causes a most regular spike activity. This phenomenon shall be termed intrinsic CR. In the presence of an applied periodic stimulus, we demonstrate that the signal-to-noise ratio (SNR) exhibits SR vs. decreasing patch size, or vs. increasing internal noise strength, respectively. Moreover, we demonstrate that conventional SR vs. the external noise intensity occurs only for sufficiently large membrane patches, when the intensity of internal noise is below its optimal level. Thus, biological SR is seemingly rooted in the collective properties of large ion channel ensembles rather than in the individual stochastic dynamics of single ion channels.

Stochastic resonance in ion channels characterized by information theory.

We identify a unifying measure for stochastic resonance (SR) in voltage dependent ion channels which comprises periodic (conventional), aperiodic, and nonstationary SR. Within a simplest setting, the gating dynamics is governed by two-state conductance fluctuations, which switch at random time points between two values. The corresponding continuous time point process is analyzed by virtue of information theory. In pursuing this goal we evaluate for our dynamics the tau information, the mutual information, and the rate of information gain. As a main result we find an analytical formula for the rate of information gain that solely involves the probability of the two channel states and their noise averaged rates. For small voltage signals it simplifies to a handy expression. Our findings are applied to study SR in a potassium channel. We find that SR occurs only when the closed state is predominantly dwelled upon. Upon increasing the probability for the open channel state the application of an extra dose of noise monotonically deteriorates the rate of information gain, i.e., no SR behavior occurs.

Effect of channel block on the spiking activity of excitable membranes in a stochastic Hodgkin-Huxley model.

The influence of intrinsic channel noise on the spontaneous spiking activity of poisoned excitable membrane patches is studied by use of a stochastic generalization of the Hodgkin-Huxley model. Internal noise stemming from the stochastic dynamics of individual ion channels is known to affect the collective properties of the whole ion channel cluster. For example, there exists an optimal size of the membrane patch for which the internal noise alone causes a regular spontaneous generation of action potentials. In addition to varying the size of ion channel clusters, living organisms may adapt the densities of ion channels in order to optimally regulate the spontaneous spiking activity. The influence of a channel block on the excitability of a membrane patch of a certain size is twofold: first, a variation of ion channel densities primarily yields a change of the conductance level; second, a down-regulation of working ion channels always increases the channel noise. While the former effect dominates in the case of sodium channel block resulting in a reduced spiking activity, the latter enhances the generation of spontaneous action potentials in the case of a tailored potassium channel blocking. Moreover, by blocking some portion of either potassium or sodium ion channels, it is possible to either increase or decrease the regularity of the spike train.

Rectification in synthetic conical nanopores: A one-dimensional Poisson-Nernst-Planck model

Ion transport in biological and synthetic nanochannels is characterized by phenomena such as ion current fluctuations and rectification. Recently, it has been demonstrated that nanofabricated synthetic pores can mimic transport properties of biological ion channels [P. Yu. Apel, Nucl. Instrum Methods Phys. Res. B 184, 337 (2001); Z. Siwy, Europhys. Lett. 60, 349 (2002)]. Here, the ion current rectification is studied within a reduced one-dimensional (1D) Poisson-Nernst-Planck (PNP) model of synthetic nanopores. A conical channel of a few nm to a few hundred nm in diameter, and of a few mum long is considered in the limit where the channel length considerably exceeds the Debye screening length. The rigid channel wall is assumed to be weakly charged. A one-dimensional reduction of the three-dimensional problem in terms of corresponding entropic effects is put forward. The ion transport is described by the nonequilibrium steady-state solution of the 1D Poisson-Nernst-Planck system within a singular perturbation treatment. An analytic formula for the approximate rectification current in the lowest order perturbation theory is derived. A detailed comparison between numerical results and the singular perturbation theory is presented. The crucial importance of the asymmetry in the potential jumps at the pore ends on the rectification effect is demonstrated. This so constructed 1D theory is shown to describe well the experimental data in the regime of small-to-moderate electric currents.

Optimal Design of Microarray Immunoassays to Compensate for Kinetic Limitations Theory and Experiment

In this report we examine the limitations of existing microarray immunoassays and investigate how best to optimize them using theoretical and experimental approaches. Derived from DNA technology, microarray immunoassays present a major technological challenge with much greater physicochemical complexity. A key physicochemical limitation of the current generation of microarray immunoassays is a strong dependence of antibody microspot kinetics on the mass flux to the spot as was reported by us previously. In this report we analyze, theoretically and experimentally, the effects of microarray design parameters (incubation vessel geometry, incubation time, stirring, spot size, antibody-binding site density, etc.) on microspot reaction kinetics and sensitivity. Using a two-compartment model, the quantitative descriptors of the microspot reaction were determined for different incubation and microarray design conditions. This analysis revealed profound mass transport limitations in the observed kinetics, which may be slowed down as much as hundreds of times compared with the solution kinetics. The data obtained were considered with relevance to microspot assay diffusional and adsorptive processes, enabling us to validate some of the underlying principles of the antibody microspot reaction mechanism and provide guidelines for optimal microspot immunoassay design. For an assay optimized to maximize the reaction velocity on a spot, we demonstrate sensitivities in the am and low fm ranges for a system containing a representative sample of antigen-antibody pairs. In addition, a separate panel of low abundance cytokines in blood plasma was detected with remarkably high signal-to-noise ratios.

Channel noise and synchronization in excitable membranes

Using a stochastic generalization of the Hodgkin–Huxley model, we consider the influence of intrinsic channel noise on the synchronization between the spiking activity of the excitable membrane and an externally applied periodic signal. For small patches, i.e., when the channel noise dominates the excitable dynamics, we find the phenomenon of intrinsic coherence resonance. In this case, the relatively regular spiking behavior is practically independent of the applied external driving; therefore no synchronization occurs. Synchronization takes place, however, only for sufficiently large ion channel assemblies. The neuronal signal processing is thus likely rooted in the collective properties of optimally large assemblies of ion channels.

Ion channel gating: A first-passage time analysis of the Kramers type

The opening rate of voltage-gated potassium ion channels exhibits a characteristic knee-like turnover where the common exponential voltage dependence changes suddenly into a linear one. An explanation of this puzzling crossover is put forward in terms of a stochastic first passage time analysis. The theory predicts that the exponential voltage dependence correlates with the exponential distribution of closed residence times. This feature occurs at large negative voltages when the channel is predominantly closed. In contrast, the linear part of voltage dependence emerges together with a nonexponential distribution of closed dwelling times with increasing voltage, yielding a large opening rate. Depending on the parameter set, the closed-time distribution displays a power law behavior that extends over several decades.

Viscoelastic subdiffusion: from anomalous to normal.

We study viscoelastic subdiffusion in bistable and periodic potentials within the generalized Langevin equation approach. Our results justify the (ultra)slow fluctuating rate view of the corresponding bistable non-Markovian dynamics which displays bursting and anticorrelation of the residence times in two potential wells. The transition kinetics is asymptotically stretched exponential when the potential barrier V0 several times exceeds thermal energy k(B)T [V(0) approximately (2-10)k(B)T] and it cannot be described by the non-Markovian rate theory (NMRT). The well-known NMRT result approximates, however, ever better with the increasing barrier height, the most probable logarithm of the residence times. Moreover, the rate description is gradually restored when the barrier height exceeds a fuzzy borderline which depends on the power-law exponent of free subdiffusion alpha . Such a potential-free subdiffusion is ergodic. Surprisingly, in periodic potentials it is not sensitive to the barrier height in the long time asymptotic limit. However, the transient to this asymptotic regime is extremally slow and it does profoundly depend on the barrier height. The time scale of such subdiffusion can exceed the mean residence time in a potential well or in a finite spatial domain by many orders of magnitude. All these features are in sharp contrast with an alternative subdiffusion mechanism involving jumps among traps with the divergent mean residence time in these traps.

Fractional diffusion modeling of ion channel gating.

An anomalous diffusion model for ion channel gating is put forward. This scheme is able to describe nonexponential, power-law-like distributions of residence time intervals in several types of ion channels. Our method presents a generalization of the discrete diffusion model by Millhauser, Salpeter, and Oswald [Proc. Natl. Acad. Sci. U.S.A. 85, 1503 (1988)] to the case of a continuous, anomalous slow conformational diffusion. The corresponding generalization is derived from a continuous-time random walk composed of nearest-neighbor jumps which in the scaling limit results in a fractional diffusion equation. The studied model contains three parameters only: the mean residence time, a characteristic time of conformational diffusion, and the index of subdiffusion. A tractable analytical expression for the characteristic function of the residence time distribution is obtained. In the limiting case of normal diffusion, our prior findings [Proc. Natl. Acad. Sci. U.S.A. 99, 3552 (2002)] are reproduced. Depending on the chosen parameters, the fractional diffusion model exhibits a very rich behavior of the residence time distribution with different characteristic time regimes. Moreover, the corresponding autocorrelation function of conductance fluctuations displays nontrivial power law features. Our theoretical model is in good agreement with experimental data for large conductance potassium ion channels.

BRIDGE-ASSISTED ELECTRON TRANSFER DRIVEN BY DICHOTOMICALLY FLUCTUATING TUNNELING COUPLING

The influence of dichotomically fluctuating tunneling coupling on long‐range electron transfer is studied theoretically. Within an approach similar to the noninteracting blip approximation known from the spin‐boson model a set of coupled integrodifferential kinetic equations is derived. These equations describe the time development of the electronic populations difference between the donor and acceptor states averaged with respect to the stochastic process and the quantum fluctuations of the bath. Furthermore, they contain the correlator between the level population difference and the fluctuating tunneling matrix element. A detailed analysis is carried out for the case of a strong coupling of the transferred electron to a single soft reaction coordinate. Within a Markovian approximation and an adiabatic removing of the correlator, the balance type kinetic equations can be derived which contain effective transfer rates. These rates depend strongly on the correlation time of fluctuations and can exhibit a r...