Homologous desensitization of human histamine H3 receptors expressed in CHO-K1 cells

Osorio-Espinoza, Angélica; Escamilla-Sánchez, Juan; Aquino‐Jarquín, Guillermo; Arias‐Montaño, José‐Antonio

doi:10.1016/j.neuropharm.2013.09.011

Cited by 19 publications

(13 citation statements)

References 55 publications

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“…homologous desensitization), which may occur after prolonged exposure to high concentrations of an agonist. 67 , 68 One possible alternative mechanism to maintain sustained pupil constriction would be a reduction in the sensitivity of the hyperpolarizing channels (e.g. K v and BKCa), which are indirectly or directly activated/opened by high cytosolic Ca 2+ .…”

Section: Discussionmentioning

confidence: 99%

Elucidation of Cellular Mechanisms That Regulate the Sustained Contraction and Relaxation of the Mammalian Iris

Sghari

Gunhaga

2020

Invest. Ophthalmol. Vis. Sci.

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Purpose In mammals, pupil constriction and dilation form the pupillary light reflex (PLR), which is mediated by both brain-regulated (parasympathetic) and local iris-driven reflexes. To better understand the cellular mechanisms that regulate pupil physiological dynamics via central and local photoreception, we have examined the regulation of the PLR via parasympathetic and local activation, respectively. Methods In this study, the PLR was examined in mouse enucleated eyes ex vivo in real-time under different ionic conditions in response to acetylcholine and/or blue light (480 nm). The use of pupillometry recordings captured the relaxation, contraction, and pupil escape (redilation) processes for 10 minutes up to 1 hour. Results Among others, our results show that ryanodine receptor channels are the main driver for iridal stimulation–contraction coupling, in which extracellular influx of Ca 2+ is required for amplification of pupil constriction. Both local and parasympathetic iridal activations are necessary, but not sufficient for sustained pupil constriction. Moreover, the degree of membrane potential repolarization in the dark is correlated with the latency and velocity of iridal constriction. Furthermore, pupil escape is driven by membrane potential hyperpolarization where voltage-gated potassium channels play a crucial role. Conclusions Together, this study presents new mechanisms regulating synchronized pupil dilation and contraction, sustained pupil constriction, iridal stimulation-contraction coupling, and pupil escape.

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Section: Discussionmentioning

confidence: 99%

Elucidation of Cellular Mechanisms That Regulate the Sustained Contraction and Relaxation of the Mammalian Iris

Sghari

Gunhaga

2020

Invest. Ophthalmol. Vis. Sci.

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“…We revisited the role of H 3 R-mediated autoinhibition in histaminergic neurons and suggest that studies reporting a missing functionality of these receptors were operating under conditions of increased receptor desensitization/internalization (Osorio-Espinoza et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…As the majority of histaminergic neurons express the TRPV1 (transient receptor potential vanilloid 1) channel (Kernder et al, 2014), whose activation by capsaicin leads to cell swelling (Pecze et al, 2013), which in turn may accelerate H 3 R internalisation (Osorio-Espinoza et al, 2014), we tested the response to the H 3 R ligand RAMH after capsaicin. In 8 Tmt-HDC neurons, which were excited by capsaicin (183 ± 40 % of control, Figure 6D) the response to RAMH 2µM was reduced (1 cell) or abolished (7 cells) ( Figure 6D).…”

Section: How Reliable Is H 3 R Autoinhibition?mentioning

confidence: 99%

Identification of histaminergic neurons through histamine 3 receptor-mediated autoinhibition

et al. 2016

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“…CHO‐K1 cells were cultured in DMEM supplemented with 10% FBS and penicillin/streptomycin at 37°C and 5% CO 2 in a humidified incubator. CHO‐K1 cells were grown to 50%–70% confluence and stably transfected with mammalian expression vector of pCI‐neo encoding the full length of human H 3 R (1,335 bp, 445 aa; Osorio‐Espinoza, Escamilla‐Sanchez, Aquino‐Jarquin, & Arias‐Montano, ) by electroporation. Briefly, after harvesting, cells were resuspended in 400 μL DMEM and transferred to an electroporation cuvette with a 0.4‐cm gap between electrodes.…”

Section: Methodsmentioning

confidence: 99%

In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H₃ receptors and cholinesterase enzymes

et al. 2019

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Recently, multi-target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H 3 receptors (H 3 Rs) and cholinesterases are involved in pathophysiology of AD, identification of dual-acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H 3 R antagonistic activity combined with anticholinesterase properties of two previously computationally identified leadpropyl]-1H-indole-2-carboxamide) and compound 4 (7-chloro-N-[(1-methylpiperidin-3-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxamide), was tested.Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (com-pound 3: H 3 R EC 50 = 0.73 nM; compound 4: H 3 R EC 50 = 31 nM) and micromolar values (compound 3: AChE IC 50 = 9.09 µM, BuChE IC 50 = 21.10 µM; compound 4: AChE IC 50 = 8.40 µM, BuChE IC 50 = 4.93 µM) for H 3 R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H 3 R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy. K E Y W O R D S anticholinesterase, anti-H 3 R agents, histamine H 3 receptor, molecular docking, molecular dynamics simulation, multi-target directed ligands 280 | GHAMARI et Al.

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Homologous desensitization of human histamine H3 receptors expressed in CHO-K1 cells

Cited by 19 publications

References 55 publications

Elucidation of Cellular Mechanisms That Regulate the Sustained Contraction and Relaxation of the Mammalian Iris

Elucidation of Cellular Mechanisms That Regulate the Sustained Contraction and Relaxation of the Mammalian Iris

Identification of histaminergic neurons through histamine 3 receptor-mediated autoinhibition

In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H₃ receptors and cholinesterase enzymes

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Homologous desensitization of human histamine H3 receptors expressed in CHO-K1 cells

Cited by 19 publications

References 55 publications

Elucidation of Cellular Mechanisms That Regulate the Sustained Contraction and Relaxation of the Mammalian Iris

Elucidation of Cellular Mechanisms That Regulate the Sustained Contraction and Relaxation of the Mammalian Iris

Identification of histaminergic neurons through histamine 3 receptor-mediated autoinhibition

In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H3 receptors and cholinesterase enzymes

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In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H₃ receptors and cholinesterase enzymes