scholarly journals Development of novel potent ligands for GPR85, an orphan G protein-coupled receptor expressed in the brain

2021 ◽  
Author(s):  
Aya Sakai ◽  
Takeshi Yasui ◽  
Masashi Watanave ◽  
Rine Tatsumi ◽  
Yoshihiko Yamamoto ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptor ◽  
Orphan Receptors ◽  
Channel Opening ◽  
Ic50 Values ◽  
The Central Nervous System ◽  
Cerebellar Purkinje Cells ◽  
Electrophysiological Technique ◽  
G Protein Coupled ◽  
The Brain

GPR85 is a member of the G protein-coupled receptor and is a super-conserved receptor expressed in the brain sub-family (SREB) with GPR27 and GPR173. These three receptors are orphan receptors; however, their endogenous ligands have not been identified. SREB has garnered the interest of many scientists because it is expressed in the central nervous system and is evolutionarily conserved. In particular, brain mass is reported to be increased and learning and memory are improved in GPR85 knockout mice (Matsumoto et al., 2008). In this study, we characterized newly synthesized compounds using a GPR85-Gsα fusion protein and the [35S]GTPδS binding assay and identified novel GPR85 inverse-agonists with IC50 values of approximately 1 μM. To analyze the neurochemical character of the compounds and investigate the physiological significance of GPR85, we used cerebellar Purkinje cells expressing GPR85 and an electrophysiological technique. Based on the results, the inverse-agonist compound for GPR85 modulated potassium channel opening. Together with the results of previous gene analysis of GPR85, we expect that the development of the GPR85 ligand will provide new insights into a few types of neurological disorders.

scholarly journals The protective role of proton-sensing TDAG8 in the brain injury in a mouse ischemia reperfusion model

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Koichi Sato ◽  
Ayaka Tobo ◽  
Chihiro Mogi ◽  
Masayuki Tobo ◽  
Nobuhiro Yamane ◽  
...  
Keyword(s):  
Cerebral Infarction ◽  
G Protein ◽  
Morphological Changes ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Cerebral Injury ◽  
G Protein Coupled Receptor ◽  
Dysfunctional Behavior ◽  
G Protein Coupled ◽  
The Brain

Abstract Extracellular acidification in the brain has been observed in ischemia; however, the physiological and pathophysiological implications of the pH reduction remain largely unknown. Here, we analyzed the roles of proton-sensing G protein-coupled receptors, including T-cell death-associated gene 8 (TDAG8), ovarian cancer G protein-coupled receptor 1 (OGR1), and G protein-coupled receptor 4 (GPR4) in a mouse ischemia reperfusion model. Cerebral infarction and dysfunctional behavior with transient middle cerebral artery occlusion (tMCAO) and subsequent reperfusion were exacerbated by the deficiency of TDAG8, whereas no significant effect was observed with the deficiency of OGR1 or GPR4. We confirmed that the pH of the predicted infarction region was 6.5. TDAG8 mRNA was observed in Iba1-positive microglia in the mouse brain. The tMCAO increased the mRNA expression of tumor necrosis factor-α in the ipsilateral cerebral hemisphere and evoked morphological changes in microglia in an evolving cerebral injury. These tMCAO-induced actions were significantly enhanced by the TDAG8 deficiency. Administration of minocycline, which is known to inhibit microglial activation, improved the cerebral infarction and dysfunctional behavior induced by tMCAO in the TDAG8-deficient mouse. Thus, acidic pH/TDAG8 protects against cerebral infarction caused by tMCAO, at least due to the mechanism involving the inhibition of microglial functions.

scholarly journals Dysfunction of G Protein-Coupled Receptor Kinases in Alzheimer’'s Disease

2010 ◽  
Vol 10 ◽  
pp. 1667-1678 ◽  
Author(s):  
William Z. Suo ◽  
Longxuan Li
Keyword(s):  
G Protein ◽  
Basal Forebrain ◽  
Brain Inflammation ◽  
G Protein Coupled Receptor ◽  
Amyloid Accumulation ◽  
Cognitive Levels ◽  
Receptor Kinases ◽  
Β Amyloid ◽  
G Protein Coupled ◽  
The Brain

Although mutations and variations of several genes have been identified to be involved in Alzheimer's disease (AD), the efforts towards understanding the pathogenic mechanisms of the disease still have a long journey to go. One such effort is to identify the signal transduction deficits, for which previous studies have suggested that the central problems appear to be at the interface between G proteins and their coupled receptors. G protein-coupled receptor kinases (GRKs) are a small family of serine/threonine protein kinases primarily acting at the “receptor-G protein interface””. Recent studies have indicated the possible involvement of GRK, primarily GRK2 and GRK5, dysfunction in the pathogenesis of AD. It seems that mild, soluble, β-amyloid accumulation can lead to a reduced membrane (functional) and an elevated cytosolic GRK2/5. The increased cytosolic GRK2 appears to be colocalized with damaged mitochondria and neurofibrillary tangles. Moreover, the total levels of GRK2, not only in the brain, but also in peripheral blood samples, are increased in a manner inversely correlated with the patient's cognitive levels. The deficiency of GRK5, on the other hand, impairs presynaptic M2 autoreceptor desensitization, which leads to a reduced acetylcholine release, axonal/synaptic degenerative changes, and associated amnestic, mild cognitive impairment. It also promotes an evil cycle to further increase Beta-amyloid accumulation and exaggerates brain inflammation, possibly even the basal forebrain cholinergic degeneration. Therefore, continuous efforts in this direction are necessary before translating the knowledge to any therapeutic strategies.

scholarly journals Effect of 5-hydroxytryptamine Receptor in the Lower Esophageal Sphincter Regulation Mechanism

2020 ◽  
Vol 3 (6) ◽  
Author(s):  
Hefei Li ◽  
Junfeng Liu ◽  
Xixuan Zhang ◽  
Zhiwei Lai ◽  
Zhen Gao ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Regulation Mechanism ◽  
Visceral Sensitivity ◽  
Gastrointestinal Dysfunction ◽  
Secretion Regulation ◽  
The Central Nervous System ◽  
Esophageal Sphincter ◽  
G Protein Coupled ◽  
The Brain

As a neurotransmitter and avascular active substance, the 5-hydroxytryptamine (5-HT, serotonin) is widely distributed in the central nervous system and surrounding tissues. The 5-HT can play its role by acting on its corresponding 5-HT receptor. Nowadays, the 5-HT receptor can be classified into seven, according to different signal transduction method of receptors, the 5-HT3 receptor belongs to the ligand-gated ion channels, while other six 5-HT receptors are involved into the G protein-coupled receptors and play the biological role by binding to specific G protein-coupled receptors (GPCRs) on the surface of the cell membrane. The 5-HT plays an important role in the brain-gut information transmission and studies showed that the physiological stimulations like having meals, and pathological stimulations like ischemia and stress could promote the release of the 5-HT. In the gastrointestinal tract, the 5-HT is closely related to gastrointestinal sensitivity, gastrointestinal movement and secretion regulation, as well as many gastrointestinal dysfunction disorders, such as gastrointestinal power and visceral sensitivity abnormality and abnormalities of brain-gut axis.

scholarly journals In vitro profiling of orphan G protein coupled receptor (GPCR) constitutive activity

2021 ◽  
Author(s):  
Lyndsay R. Watkins ◽  
Cesare Orlandi
Keyword(s):  
G Protein ◽  
Luciferase Reporter ◽  
List Type ◽  
Constitutive Activity ◽  
Protein Signaling ◽  
G Protein Coupled Receptor ◽  
Orphan Receptors ◽  
Gpcr Family ◽  
Orphan Gpcrs ◽  
G Protein Coupled

AbstractBackground and PurposeMembers of the G protein coupled receptor (GPCR) family are targeted by a significant fraction of the available FDA-approved drugs. However, the physiological role and pharmacological properties of many GPCRs remain unknown, representing untapped potential in drug design. Of particular interest are ~100 less-studied GPCRs known as orphans because their endogenous ligands are unknown. Intriguingly, disease-causing mutations identified in patients, together with animal studies, have demonstrated that many orphan receptors play crucial physiological roles, and thus, represent attractive drug targets.Experimental ApproachThe majority of deorphanized GPCRs demonstrate coupling to Gi/o, however a limited number of techniques allow the detection of intrinsically small constitutive activity associated with Gi/o protein activation which represents a significant barrier in our ability to study orphan GPCR signaling. Using luciferase reporter assays, we effectively detected constitutive Gs, Gq, and G12/13 protein signaling by unliganded receptors, and introducing various G protein chimeras, we provide a novel, highly-sensitive tool capable of identifying Gi/o coupling in unliganded orphan GPCRs.Key ResultsUsing this approach, we measured the constitutive activity of the entire class C GPCR family that includes 8 orphan receptors, and a subset of 20 prototypical class A GPCR members, including 11 orphans. Excitingly, this approach illuminated the G protein coupling profile of 8 orphan GPCRs (GPR22, GPR137b, GPR88, GPR156, GPR158, GPR179, GPRC5D, and GPRC6A) previously linked to pathophysiological processes.Conclusion and ImplicationsWe provide a new platform that could be utilized in ongoing studies in orphan receptor signaling and deorphanization efforts.What is already knownA large group of understudied orphan GPCRs controls a variety of physiological process.What this study addsA new strategy to identify G protein signaling associated with orphan GPCRs.Identification of Gi/o coupling for 8 orphan GPCRs.What is the clinical significanceMany orphan GPCRs are associated with pathological conditions and represent promising druggable targets.

scholarly journals The GRK2 Overexpression Is a Primary Hallmark of Mitochondrial Lesions during Early Alzheimer Disease

2009 ◽  
Vol 2009 ◽  
pp. 1-14 ◽  
Author(s):  
Mark E. Obrenovich ◽  
Hector H. Palacios ◽  
Eldar Gasimov ◽  
Jerzy Leszek ◽  
Gjumrakch Aliev
Keyword(s):  
Alzheimer Disease ◽  
G Protein ◽  
A Priori ◽  
Vascular Complications ◽  
Pharmacological Intervention ◽  
G Protein Coupled Receptor ◽  
Brain Connection ◽  
G Protein Coupled ◽  
The Brain

Increasing evidence points to vascular damage as an early contributor to the development of two leading causes of age-associated dementia, namely Alzheimer disease (AD) and AD-like pathology such as stroke. This review focuses on the role of G protein-coupled receptor kinases (GRKs) as they relate to dementia and how the cardio and cerebrovasculature is involved in AD pathogenesis. The exploration of GRKs in AD pathogenesis may help bridge gaps in our understanding of the heart-brain connection in relation to neurovisceral damage and vascular complications of AD. The a priori basis for this inquiry stems from the fact that kinases of this family regulate numerous receptor functions in the brain, myocardium and elsewhere. The aim of this review is to discuss the finding of GRK2 overexpression in the context of early AD pathogenesis. Also, we consider the consequences for this overexpression as a loss of G-protein coupled receptor (GPCR) regulation, as well as suggest a potential role for GPCRs and GRKs in a unifying theory of AD pathogenesis through the cerebrovasculature. Finally, we synthesize this newer information in an attempt to put it into context with GRKs as regulators of cellular function, which makes these proteins potential diagnostic and therapeutic targets for future pharmacological intervention.

Sign in / Sign up

Export Citation Format

Share Document