Inhibitory effect of amiloride and gadolinium on fine afferent nerves in the rat knee: evidence of mechanogated ion channels in joints

Voltage-gated ion channels mediate electrical dynamics in excitable tissues and are an important class of drug targets. Channels can gate in sub-millisecond timescales, show complex manifolds of conformational states, and often show state-dependent pharmacology. Mechanistic studies of ion channels typically involve sophisticated voltage-clamp protocols applied through manual or automated electrophysiology. Here, we develop all-optical electrophysiology techniques to study activity-dependent modulation of ion channels, in a format compatible with high-throughput screening. Using optical electrophysiology, we recapitulate many voltage-clamp protocols and apply to Nav1.7, a channel implicated in pain. Optical measurements reveal that a sustained depolarization strongly potentiates the inhibitory effect of PF-04856264, a Nav1.7-specific blocker. In a pilot screen, we stratify a library of 320 FDA-approved compounds by binding mechanism and kinetics, and find close concordance with patch clamp measurements. Optical electrophysiology provides a favorable tradeoff between throughput and information content for studies of NaV channels, and possibly other voltage-gated channels.

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Inhibitory effects on intake of cholecystokinin-8 and cholecystokinin-33 in rats with hepatic proper or common hepatic branch vagal innervation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00062.2005 ◽

2005 ◽

Vol 289 (2) ◽

pp. R456-R462 ◽

Cited By ~ 23

Author(s):

S. Eisen ◽

R. J. Phillips ◽

N. Geary ◽

E. A. Baronowsky ◽

T. L. Powley ◽

...

Keyword(s):

Intraperitoneal Administration ◽

Inhibitory Effect ◽

Inhibitory Interaction ◽

Afferent Nerves ◽

Afferent Fibers ◽

Vagal Nerves ◽

Vagal Innervation ◽

Afferent Vagal ◽

Vagal Afferent ◽

Hepatic Branch

The relative potencies of cholecystokinin (CCK)-8 and CCK-33 for decreasing meal size depend on the route of administration. Inhibitory potencies are equal after intraperitoneal administration, but CCK-33 is significantly more potent after intraportal administration. This suggests that CCK-33 is a more effective stimulant of hepatic afferent vagal nerves than is CCK-8. To investigate this possibility, we administered both peptides intraperitoneally in rats with abdominal vagotomies that spared only the hepatic proper vagal nerves (H) and in rats with abdominal vagotomies that spared the common hepatic branch that contains the fibers of the hepatic proper and gastroduodenal nerves (HGD). The vagal afferent innervation in H and HGD rats was verified with a wheat germ agglutinin-horseradish tracer strategy. Intraperitoneal administration of CCK-33 decreased 30-min intake of 10% sucrose in H rats as much as in sham rats, but CCK-8 decreased intake significantly less in H rats than in sham rats. The larger inhibitory effect of CCK-33 than of CCK-8 in H rats is consistent with the hypothesis that CCK-33 is a more effective stimulant of the hepatic proper vagal afferent nerves than CCK-8. In contrast to the results in H rats, the inhibitory potencies of both peptides were significantly and equivalently reduced in HGD rats compared with sham rats. This suggests that there is an inhibitory interaction between the stimulation of the gastroduodenal and hepatic proper afferent fibers by CCK-33.

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Ion channels and membrane potential in stimulus–secretion coupling in adrenal paraneurons

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y84-077 ◽

1984 ◽

Vol 62 (5) ◽

pp. 477-483 ◽

Cited By ~ 10

Author(s):

Daniel L. Kilpatrick

Keyword(s):

Membrane Potential ◽

Ion Channels ◽

Adrenal Medulla ◽

Nicotinic Receptor ◽

Calcium Influx ◽

Inhibitory Effect ◽

Muscle Membrane ◽

Bovine Adrenal Medulla ◽

Voltage Dependent ◽

Stimulus Secretion Coupling

Cultured bovine adrenal medulla cells have been shown to contain several different ion channels (Na+, Ca2+ acetylcholine receptor regulated) whose activation leads to the secretion of catecholamines. The pharmacology of these ion channels and their interactions during secretion have been examined. The mechanisms of agonist-induced calcium influx are of particular interest since this is an early obligatory event during secretion from the adrenal medulla. Data obtained on catecholamine release and 45Ca2+ uptake indicate that both voltage-dependent and voltage-independent calcium influx mechanisms operate in cultured bovine adrenal medulla cells. The significance of these results in understanding the mechanism of action of the physiological stimulus acetylcholine (Ach) will be discussed. The alkaloid channel neurotoxins D-600, batrachotoxin, veratridine, and aconitine were shown to exert a noncompetitive inhibitory effect on Ach-induced ion flux in adrenal medulla cells, presumably through an interaction with the nicotinic receptor regulated channel. Lipid-soluble neurotoxins may interact with multiple ion channels in nerve and muscle membrane.

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The Effect of Hydrophobic Monoamines on Acid-Sensing Ion Channels ASIC1B

Acta Naturae ◽

10.32607/20758251-2015-7-2-95-101 ◽

2015 ◽

Vol 7 (2) ◽

pp. 95-101 ◽

Cited By ~ 5

Author(s):

E. I. Nagaeva ◽

N. N. Potapieva ◽

D. B. Tikhonov

Keyword(s):

Ion Channels ◽

Patch Clamp ◽

Inhibitory Effect ◽

Hill Coefficient ◽

Patch Clamp Technique ◽

Recombinant Receptors ◽

Whole Cell Patch Clamp ◽

Acid Sensing Ion Channels ◽

The Hill ◽

Cooperative Activation

Acid-sensing ion channels (ASICs) are widely distributed in both the central and peripheral nervous systems of vertebrates. The pharmacology of these receptors remains poorly investigated, while the search for new ASIC modulators is very important. Recently, we found that some monoamines, which are blockers of NMDA receptors, inhibit and/or potentiate acid-sensing ion channels, depending on the subunit composition of the channels. The effect of 9-aminoacridine, IEM-1921, IEM-2117, and memantine both on native receptors and on recombinant ASIC1a, ASIC2a, and ASIC3 homomers was studied. In the present study, we have investigated the effect of these four compounds on homomeric ASIC1b channels. Experiments were performed on recombinant receptors expressed in CHO cells using the whole-cell patch clamp technique. Only two compounds, 9-aminoacridine and memantine, inhibited ASIC1b channels. IEM-1921 and IEM-2117 were inactive even at a 1000 M concentration. In most aspects, the effect of the compounds on ASIC1b was similar to their effect on ASIC1a. The distinguishing feature of homomeric ASIC1b channels is a steep activation-dependence, indicating cooperative activation by protons. In our experiments, the curve of the concentration dependence of ASIC1b inhibition by 9-aminoacridine also had a slope (Hill coefficient) of 3.8, unlike ASIC1a homomers, for which the Hill coefficient was close to 1. This finding indicates that the inhibitory effect of 9-aminoacridine is associated with changes in the activation properties of acid-sensing ion channels.

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371 Selective inhibitory effect of 5-hydroxymethyl tolterodine (5-HMT), an active metabolite of fesoterodine, on capsaicin-sensitive C-fibers among the primary bladder mechanosensitive afferent nerves in the rat

European Urology Supplements ◽

10.1016/s1569-9056(14)60366-3 ◽

2014 ◽

Vol 13 (1) ◽

pp. e371-e371b

Author(s):

N. Aizawa ◽

Y. Homma ◽

Y. Igawa

Keyword(s):

Active Metabolite ◽

Inhibitory Effect ◽

C Fibers ◽

Afferent Nerves ◽

Primary Bladder

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Post-Stimulation Inhibitory Effect on Reflex Bladder Activity Induced by Activation of Somatic Afferent Nerves in the Foot

The Journal of Urology ◽

10.1016/j.juro.2011.09.012 ◽

2012 ◽

Vol 187 (1) ◽

pp. 338-343 ◽

Cited By ~ 17

Author(s):

Guoqing Chen ◽

Jeffrey A. Larson ◽

P. Dafe Ogagan ◽

Bing Shen ◽

Jicheng Wang ◽

...

Keyword(s):

Inhibitory Effect ◽

Afferent Nerves ◽

Bladder Activity

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Selective Inhibitory Effect of Imidafenacin and 5-Hydroxymethyl Tolterodine on Capsaicin Sensitive C Fibers of the Primary Bladder Mechanosensitive Afferent Nerves in the Rat

The Journal of Urology ◽

10.1016/j.juro.2014.09.005 ◽

2015 ◽

Vol 193 (4) ◽

pp. 1423-1432 ◽

Cited By ~ 10

Author(s):

Naoki Aizawa ◽

Hiroki Ito ◽

Rino Sugiyama ◽

Tetsuya Fujimura ◽

Motofumi Suzuki ◽

...

Keyword(s):

Inhibitory Effect ◽

C Fibers ◽

Afferent Nerves ◽

Primary Bladder

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The Role of K+ And Ca2+ Ion Channels in Α-Terpinyle Acetate-Induced Vasodilation in Rat’s Aortic Rings

Science Journal of University of Zakho ◽

10.25271/2017.5.2.362 ◽

2017 ◽

Vol 5 (2) ◽

pp. 162

Author(s):

Dlzar A. Kheder ◽

Omar A. M. Al-Habib ◽

Lina N. Adam

Keyword(s):

Ion Channels ◽

Signal Transduction Pathway ◽

Aortic Ring ◽

Katp Channels ◽

Inhibitory Effect ◽

K Channel ◽

Transduction Pathway ◽

Aromatic Plants ◽

Vasodilatory Effect

The monoterpene, α-terpinyle acetate (TA) is a constituent of essential oils present in aromatic plants. Since the role of ion channels and endothelial hyperpolarizing factors in TA induced relaxation in rat’s aorta is unknown, the current study aimed to study the mechanism underlying the vasodilatory effect of TA in isolated aortic rings. Terpinyle acetate induced a potent vasodilation in rat aortic rings with a percentage of relaxation of 63.79 %. The results of the role of K+ channel subtypes in vasorelaxation revealed that both Kv and KATP played a major role since GLIB produced a maximum percent of inhibition in the relaxation produced by TA to 8.91 %; this was followed by 4-AP in which the percent of inhibition reduced to 14.95. On the other hand, Kir played no role in the TA induced vasorelaxation since BaCl2 did not produce any inhibition in aortic relaxation. Furthermore, also L-type Ca2+ channel played no role in TA induced relaxation since the L-type Ca2+ channel inhibitor Nifedipine did not reduce the percent of relaxation. Endothelium also played a considerable role in the induced vasorelaxation since, in denuded aorta, the percent of relaxation was reduced to 36%. Preincubation of the aortic ring with methylene blue, a soluble cGMP inhibitor also significantly reduced the TA induced relaxation to 16.39%. In contrast, preincubation with cyclooxygenase inhibitor Indomethacin did not produce any inhibitory effect on AT induced vasorelaxation. It can be concluded from these novel results that AT induced vasorelaxation involve the activation of KV, KATP channels and at least partly dependent on endothelium via the activation NO-cGMP signal transduction pathway.

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