HCAR2 Membrane Protein Introduction

Introduction of HCAR2

HCAR2, also known as niacin receptor 1 (NIACR1) and GPR109A, is a membrane protein belongs to the G-protein-coupled receptor (GPCR) family. In human, it is encoded by HCAR2 gene, and defined as a member of the nicotinic acid receptor family of GPCRs. HCAR2 acts as a high-affinity receptor for both nicotinic acid (niacin) and (D)-beta-hydroxybutyrate. The rank order of potency for the displacement of nicotinic acid binding is 5-methyl pyrazole-3-carboxylic acid = pyridine-3-acetic acid > acifran > 5-methyl nicotinic acid = acipimox > nicotinuric acid = nicotinamide.

Function of HCAR2 Membrane Protein

HCAR2 is involved in several biological pathways and plays different roles in them. After binding to nicotinic acid (niacin) or (D)-beta-hydroxybutyrate, HCAR2 mediates decreased lipolysis and increased adiponectin secretion by Gi-protein-mediated inhibition of adenylyl cyclase. This pharmacological effect calls for a relatively higher nicotinic acid doses, compared with those provided by a normal diet. HCAR2 also mediates nicotinic acid-induced apoptosis in mature neutrophils. The activation of HCAR2 by nicotinic acid leads to reduced cAMP levels, which may have an effect on the activity of cAMP-dependent protein kinase A and the phosphorylation of target proteins, resulting in neutrophil apoptosis. HCA2 activation also inhibits lipolytic and the development of atherosclerosis induces vasodilation and is involved in the niacin-induced flushing. HCA2 is a significant biomolecular target for the treatment of dyslipidemia and to increase HDL cholesterol. Furthermore, HCA2 has also been identified as a potential therapeutic target for treating neuroimmune disorders such as multiple sclerosis and Parkinson's disease.

Fig .1 Secondary structure of the human nicotinic acid receptorHCAR2. (Tunaru,2005)

Application of HCAR2 Membrane Protein in Literature

1. Chen Y., et al. β-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway. J Hepatol. 2018, pii: S0168-8278(18)32012-9. PubMed ID: 29705237
   
   

   The results of this article showed that BHB production during excess alcohol consumption has an anti-inflammatory and hepatoprotective role through an Hcar2 dependent pathway.

2. Liang Y., et al. Probiotic mixture of Lactobacillus and Bifidobacterium alleviates systemic adiposity and inflammation in non-alcoholic fatty liver disease rats through Gpr109a and the commensal metabolite butyrate. Inflammopharmacology. 2018. PubMed ID: 29633106
   
   

   This article suggested that probiotic mixture might inhibit systemic adiposity and inflammation through Gpr109a and the commensal metabolite butyrate in response to the insult of HFD.

3. Bhatt B., et al. Gpr109a limits microbiota-induced IL-23 production to constrain ILC3-mediated colonic inflammation. Biochemistry (Mosc). 2018, 200(8): 2905-2914. PubMed ID: 29514953
   
   

   Authors in this group presented a model suggesting that targeting Gpr109a will be potentially beneficial in the suppression of IL-23-mediated immunopathologies.

4. Masuda Y., et al. Overexpressing human GPR109A leads to pronounced reduction in plasma triglyceride levels in BAC transgenic rats. Development. 2018, 272: 182-192. PubMed ID: 29625294
   
   

   This article focuses on whether GPR109A activation can lead to plasma lipid changes. It showed that GPR109A signaling can lead to a reduction in triglyceride and insulin levels, and that the triglyceride-lowering effect of nicotinic acid was at least partially mediated by GPR109A signaling.

5. Parodi B., et al. Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS. ActaNeuropathol. 2015, 130(2): 279-95. PubMed ID: 25920452
   
   

   Findings of this article, whereby DMF-induced activation of a new HCAR2-dependent pathway on microglia led to the modulation of neuroinflammation and restored synaptic alterations occurring in EAE, indicating a possible novel mechanism of action for DMF in MS.

HCAR2 Preparation Options

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Reference

1. Tunaru S, et al. (2005). Characterization of determinants of ligand binding to the nicotinic acid receptor GPR109A (HM74A/PUMA-G). Molecular pharmacology. 68(5), pp. 1271-1280.

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