Last update 01 Nov 2024

mAChRs x ORAI1

Last update 01 Nov 2024

Basic Info

Related Targets

mAChRsORAI1

Drugs associated with mAChRs x ORAI1

Difenidol Hydrochloride/Scopolamine Hydrobromide Hydrate/Riboflavin

Target

ORAI1 x mAChRs

Mechanism

ORAI1 inhibitors [+1]

Active Org.

BINEX Co., Ltd.

Originator Org.

BINEX Co., Ltd.

Active Indication

Motion Sickness

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date16 Jan 2024

100 Clinical Results associated with mAChRs x ORAI1

100 Translational Medicine associated with mAChRs x ORAI1

0 Patents (Medical) associated with mAChRs x ORAI1

Literatures (Medical) associated with mAChRs x ORAI1

01 Dec 2014·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

Involvement of store-operated Ca2+ entry in activation of AMP-activated protein kinase and stimulation of glucose uptake by M3 muscarinic acetylcholine receptors in human neuroblastoma cells

Article

Author: Onali, Pierluigi ; Olianas, Maria C ; Dedoni, Simona

Gq/11-coupled muscarinic acetylcholine receptors (mAChRs) belonging to M1, M3 and M5 subtypes have been shown to activate the metabolic sensor AMP-activated protein kinase (AMPK) through Ca(2+)/calmodulin-dependent protein kinase kinase-β (CaMKKβ)-mediated phosphorylation at Thr172. However, the source of Ca(2+) required for this response has not been yet elucidated. Here, we investigated the involvement of store-operated Ca(2+) entry (SOCE) in AMPK activation by pharmacologically defined M3 mAChRs in human SH-SY5Y neuroblastoma cells. In Ca(2+)-free medium the cholinergic agonist carbachol (CCh) caused a transient increase of phospho-Thr172 AMPK that rapidly ceased within 2min. Conversely, in the presence of extracellular Ca(2+) CCh-induced AMPK phosphorylation lasted for at least 180min. The SOCE modulator 2-aminoethoxydiphephenyl borate (2-APB), at a concentration (50μM) that suppressed CCh-induced intracellular Ca(2+) ([Ca(2+)]i) plateau, inhibited CCh-induced AMPK phosphorylation. CCh triggered the activation of the endoplasmic reticulum Ca(2+) sensor stromal interaction molecule (STIM) 1, as indicated by redistribution of STIM1 immunofluorescence into puncta, and promoted the association of STIM1 with the SOCE channel component Orai1. Cell depletion of STIM1 by siRNA treatment reduced both CCh-induced [Ca(2+)]i plateau and AMPK activation. M3 mAChRs increased glucose uptake and this response required extracellular Ca(2+) and was inhibited by 2-APB, STIM1 knockdown, CaMKKβ and AMPK inhibitors, and adenovirus infection with dominant negative AMPK. Thus, the study provides evidence that SOCE is required for sustained activation of AMPK and stimulation of downstream glucose uptake by M3 mAChRs and suggests that SOCE is a critical process connecting M3 mAChRs to the control of neuronal energy metabolism.

01 Mar 2014·The Journal of PhysiologyQ2 · MEDICINE

Role of Orai1 and store‐operated calcium entry in mouse lacrimal gland signalling and function

Q2 · MEDICINE

Article

Author: Xing, Juan ; Petranka, John G. ; Davis, Felicity M. ; Bird, Gary S. ; Desai, Pooja N. ; Putney, James W.

Key points

Lacrimal acinar cells from mice whose gene for Orai1 has been deleted have no detectable store‐operated Ca2+ entry, whether assessed by measurement of cytoplasmic Ca2+ changes or as a store‐operated current.

Mice lacking Orai1 have diminished lacrimal fluid secretion in response to muscarinic–cholinergic stimulation.

Mice lacking Orai1 also show diminished exocytosis, both in vivo and in vitro.

The development and morphology of lacrimal glands, as well as responses not dependent on Ca2+ entry were unchanged in the knockout mice.

The results demonstrate the central importance of store‐operated Ca2+ entry in lacrimal exocrine function, and suggest possible strategies for combating diseases associated with diminished lacrimal secretion.

AbstractLacrimal glands function to produce an aqueous layer, or tear film, that helps to nourish and protect the ocular surface. Lacrimal glands secrete proteins, electrolytes and water, and loss of gland function can result in tear film disorders such as dry eye syndrome, a widely encountered and debilitating disease in ageing populations. To combat these disorders, understanding the underlying molecular signalling processes that control lacrimal gland function will give insight into corrective therapeutic approaches. Previously, in single lacrimal cells isolated from lacrimal glands, we demonstrated that muscarinic receptor activation stimulates a phospholipase C‐coupled signalling cascade involving the inositol trisphosphate‐dependent mobilization of intracellular calcium and the subsequent activation of store‐operated calcium entry (SOCE). Since intracellular calcium stores are finite and readily exhausted, the SOCE pathway is a critical process for sustaining and maintaining receptor‐activated signalling. Recent studies have identified the Orai family proteins as critical components of the SOCE channel activity in a wide variety of cell types. In this study we characterize the role of Orai1 in the function of lacrimal glands using a mouse model in which the gene for the calcium entry channel protein, Orai1, has been deleted. Our data demonstrate that lacrimal acinar cells lacking Orai1 do not exhibit SOCE following activation of the muscarinic receptor. In comparison with wild‐type and heterozygous littermates, Orai1 knockout mice showed a significant reduction in the stimulated tear production following injection of pilocarpine, a muscarinic receptor agonist. In addition, calcium‐dependent, but not calcium‐independent exocytotic secretion of peroxidase was eliminated in glands from knockout mice. These studies indicate a critical role for Orai1‐mediated SOCE in lacrimal gland signalling and function.

15 Mar 2007·The Journal of PhysiologyQ2 · MEDICINE

Role of the store‐operated calcium entry proteins Stim1 and Orai1 in muscarinic cholinergic receptor‐stimulated calcium oscillations in human embryonic kidney cells

Q2 · MEDICINE

Article

Author: Barbara Wedel ; Gary S. Bird ; Rebecca R. Boyles ; James W. Putney

We have investigated the nature of the Ca2+ entry supporting [Ca2+]i oscillations in human embryonic kidney (HEK293) cells by examining the roles of recently described store‐operated Ca2+ entry proteins, Stim1 and Orai1. Knockdown of Stim1 by RNA interference (RNAi) reduced the frequency of [Ca2+]i oscillations in response to a low concentration of methacholine to the level seen in the absence of external Ca2+. However, knockdown of Stim1 did not block oscillations in canomical transient receptor potential 3 channel (TRPC3)‐expressing cells and did not affect Ca2+ entry in response to arachidonic acid. The effects of knockdown of Stim1 could be reversed by inhibiting Ca2+ extrusion with a high concentration of Gd3+, or by rescuing the knockdown by overexpression of Stim1. Similarly, knockdown of Orai1 abrogated [Ca2+]i oscillations, and this was reversed by use of high concentrations of Gd3+; however, knockdown of Orai1 did not affect arachidonic acid‐activated entry. RNAi targeting 34 members of the transient receptor potential (TRP) channel superfamily did not reveal a role for any of these channel proteins in store‐operated Ca2+ entry in HEK293 cells. These findings indicate that the Ca2+ entry supporting [Ca2+]i oscillations in HEK293 cells depends upon the Ca2+ sensor, Stim1, and calcium release‐activated Ca2+ channel protein, Orai1, and provide further support for our conclusion that it is the store‐operated mechanism that plays the major role in this pathway.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis