Blocker State Dependence and Trapping in Hyperpolarization-Activated Cation Channels

Shin, Ki Soon; Rothberg, Brad S.; Yellen, Gary

doi:10.1085/jgp.117.2.91

Cited by 161 publications

(192 citation statements)

References 55 publications

(78 reference statements)

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“…5, A and B). In responses to strongly hyperpolarizing voltages, some unblocking of ZD7288 occurred with time as has also been observed in other types of neurons (Harris and Constanti 1995;Shin et al 2001). The I inst -V plot shows that g input at -62 mV in the T stellate cell was reduced from 10.4 to 4.4 nS and in the D stellate cell from 10.1 to 6.1 nS (Fig.…”

Section: Pharmacological Block By Zd7288 and Cs ϩsupporting

confidence: 71%

Hyperpolarization-Activated Currents Regulate Excitability in Stellate Cells of the Mammalian Ventral Cochlear Nucleus

Rodrigues¹,

Oertel²

2006

Journal of Neurophysiology

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Rodrigues, Aldo Rogelis A. and Donata Oertel. Hyperpolarizationactivated currents regulate excitability in stellate cells of the mammalian ventral cochlear nucleus. J Neurophysiol 95: 76 -87, 2006. First published September 28, 2005 doi:10.1152/jn.00624.2005. The differing biophysical properties of neurons the axons of which form the different pathways from the ventral cochlear nucleus (VCN) determine what acoustic information they can convey. T stellate cells, excitatory neurons the axons of which project locally and to the inferior colliculus, and D stellate cells, inhibitory neurons the axons of which project to the ipsi-and contralateral cochlear nuclei, fire tonically when they are depolarized, and, unlike other cell types in the VCN, their firing rates are sensitive to small changes in resting currents. In both types of neurons, the hyperpolarization-activated current (I h ) reversed at -40 mV, was activated at voltages negative to Ϫ60 mV, and half-activated at approximately Ϫ88 mV; maximum hyperpolarization-activated conductances (g h max ) were 19.1 Ϯ 2.3 nS in T and 30.3 Ϯ 2.6 nS in D stellate cells (means Ϯ SE). Activation and deactivation were slower in T than in D stellate cells. In both types of stellate cells, 50 M 4(N-ethyl-N-phenylamino)1,2-dimethyl-6-(methylamino) pyridinium chloride (ZD7288) and 2 mM Cs ϩ blocked a 6-to 10-fold greater conductance than the voltage-dependent g h determined from Boltzmann analyses at -62 mV. The voltageinsensitive, ZD7288-sensitive conductance was proportional to g h max and g input . 8-Br-cAMP shifted the voltage dependence of I h in the depolarizing direction, increased the rate of activation, and slowed its deactivation in both T and D stellate cells. Reduction in temperature did not change the voltage dependence but reduced the maximal g h with a Q 10 of 1.3 and slowed the kinetics with a Q 10 of 3.3.

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Section: Pharmacological Block By Zd7288 and Cs ϩsupporting

confidence: 71%

Hyperpolarization-Activated Currents Regulate Excitability in Stellate Cells of the Mammalian Ventral Cochlear Nucleus

Rodrigues¹,

Oertel²

2006

Journal of Neurophysiology

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“…In n ϭ 6 cells, the mean time constants of current activation at Ϫ100 mV in control, in the early fraction of Ͼ25-s long steps to -100 mV during drug perfusion (3 M), and on return from the long-step protocol were: 215 Ϯ 15, 237 Ϯ 28, and 213 Ϯ 14 ms, respectively, whereas the slow increase at Ϫ100 mV had a time constant of 7.0 Ϯ 0.5 s. These data indicate that ivabradine, as has been proposed for UL-FS49 and ZD7288 (Goethals et al, 1993;DiFrancesco, 1994;Shin et al, 2001), binds to the channel blocking site less favorably at hyperpolarized than at depolarized voltages.…”

Section: R E S U L T Ssupporting

confidence: 64%

“…As well as a dependence on the open/closed state of f-channels, block due to molecules such as UL-FS49 and ZD7288 also displays a voltage dependence, with hyperpolarization favoring the unblocking process (DiFrancesco, 1994;Shin et al, 2001).…”

Section: R E S U L T Smentioning

confidence: 99%

“…Like ivabradine, other I f -blocking molecules such as UL-FS49 and ZD7288 have been reported to cause a voltage-dependent block whose efficiency increases at more positive potentials (DiFrancesco, 1994;Shin et al, 2001). However, the action of ivabradine is peculiar in that a relatively sharp change of fractional block appears when going from voltages where the current is just inward (i.e., Ϫ20 mV) to voltages where the current is just outward (i.e., Ϫ10 mV); the block at deactivating voltages then seems to level up to a constant value of ‫.65.0ف‬ This behavior differs from that of a purely voltage-dependent block mechanism, such as those attributable to charged molecules entering the pore for a fraction of the membrane voltage drop (Hille, 2000), according to which the current inhibition would be expected to increase smoothly at more depolarized potentials up to full block.…”

Section: R E S U L T Smentioning

confidence: 99%

“…Several f-channel blocker molecules have been developed, such as UL-FS49 (Goethals et al, 1993;DiFrancesco, 1994), ZD7288 (BoSmith et al, 1993;Gasparini and DiFrancesco, 1997;Shin et al, 2001), and ivabradine (Thollon et al, 1994;Bois et al, 1996). These molecules have been shown to induce heart rate slowing with limited inotropic side effects, and have therefore a potential for therapeutic application in those cases where it is useful to slow heart rate without altering other cardiovascular functions.…”

Section: Introductionmentioning

confidence: 99%

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Abstracts of Papers at the Fifty-Sixth Annual Meeting of the Society of General Physiologists

2002

The Journal of General Physiology

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"Funny" (f-) channels have a key role in generation of spontaneous activity of pacemaker cells and mediate autonomic control of cardiac rate; f-channels and the related neuronal h-channels are composed of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel subunits. We have investigated the block of f-channels of rabbit cardiac sino-atrial node cells by ivabradine, a novel heart rate-reducing agent. Ivabradine is an open-channel blocker; however, block is exerted preferentially when channels deactivate on depolarization, and is relieved by long hyperpolarizing steps. These features give rise to use-dependent behavior. In this, the action of ivabradine on f-channels is similar to that reported of other rate-reducing agents such as UL-FS49 and ZD7288. However, other features of ivabradine-induced block are peculiar and do not comply with the hypothesis that the voltage-dependence of block is entirely attributable to either the sensitivity of ivabradine-charged molecules to the electrical field in the channel pore, or to differential affinity to different channel states, as has been proposed for UL-FS49 (DiFrancesco, D. 1994. Pflugers Arch. 427:64-70) and ZD7288 (Shin, S.K., B.S. Rotheberg, and G. Yellen. 2001. J. Gen. Physiol. 117:91-101), respectively. Experiments where current flows through channels is modified without changing membrane voltage reveal that the ivabradine block depends on the current driving force, rather than voltage alone, a feature typical of block induced in inwardly rectifying K ϩ channels by intracellular cations. Bound drug molecules do not detach from the binding site in the absence of inward current through channels, even if channels are open and the drug is therefore not "trapped" by closed gates. Our data suggest that permeation through f-channel pores occurs according to a multiion, single-file mechanism, and that block/unblock by ivabradine is coupled to ionic flow. The use-dependence resulting from specific features of I f block by ivabradine amplifies its rate-reducing ability at high spontaneous rates and may be useful to clinical applications.

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The “Funny” Pacemaker Current

Barbuti¹,

Bucchi²,

Baruscotti³

et al. 2009

Novel Therapeutic Targets for Antiarrhythmic Drugs

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Blocker State Dependence and Trapping in Hyperpolarization-Activated Cation Channels

Cited by 161 publications

References 55 publications

Hyperpolarization-Activated Currents Regulate Excitability in Stellate Cells of the Mammalian Ventral Cochlear Nucleus

Hyperpolarization-Activated Currents Regulate Excitability in Stellate Cells of the Mammalian Ventral Cochlear Nucleus

Abstracts of Papers at the Fifty-Sixth Annual Meeting of the Society of General Physiologists

The “Funny” Pacemaker Current

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