HCAR1 Membrane Protein Introduction

Introduction of HCAR1

HCAR1 is a receptor for the glycolytic product 2-hydroxy-propionate (lactate) and it belongs to the hydroxy-carboxylic acid (HCA) receptors. It was firstly found and identified as orphan receptor GPR81. The gene coding for HCAR1 is located on human chromosome 12q24.31. Studies have shown that HCAR1 is predominantly expressed in adipose tissues. It is also detectable at lower levels in liver, kidney, skeletal muscle, brain and pituitary. Like other HCA receptors, HCAR1 couples to Gi/Go-type G proteins, the activation of which results in decreased adenylyl cyclase activity and decreased production of cAMP. In adipocytes, cAMP is an important second messenger to induce lipolysis by activation protein kinase A, which in turn phosphorylates and activates lipolytic enzymes.

Functions of HCAR1 Membrane Protein

Several lines of evidence have shown that HCAR1 mediate lactate-induced inhibition of lipolysis in primary adipocytes as well as in mice. In HCAR1-deficient mice, the insulin-induced decrease in cAMP and insulin-induced inhibition of lipolysis were strongly reduced. Similarly, the anti-lipolytic effects of insulin on isolated adipocytes incubated in the presence of high glucose were greatly reduced in HCAR1-deficient adipocytes. As a result, lactate and HCAR1 function in an autocrine and paracrine loop to mediate insulin-induced inhibition of lipolysis in the fed state. Antagonists of HCAR1 are regarded to be of pharmacotherapeutic potential and worth exploration. Besides, HCAR1 presence was reported to enhance pancreatic cancer cell growth and metastasis and is necessary for the survival of the HER2-positive and the triple-negative breast cancer cells.

Fig.1 Model of the physiological function of the HCA1 receptor. (Ahmed, 2011)

Applications of HCAR1 Membrane Protein in Literature

1. Herrera-López G and Galván E J. Modulation of hippocampal excitability via the Hydroxycarboxylic Acid Receptor 1. Hippocampus. 2018. PubMed ID: 29704292
   
   

   This article investigated the role of lactate and its receptor, hydroxycarboxylic acid receptor 1 (HCA1), in the neuronal excitability modulation. The results showed that HCA1 appeared to function as a negative feedback for lactate.

2. Morland C., et al. The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: Expression and action in brain. Journal of Neuroscience Research. 2015, 93(7): 1045-1055. PubMed ID: 25881750
   
   

   This study investigated the expression and the role of GPR81 in the cerebral neocortex and the hippocampus of the mammalian brain. Lactate, by binding to HCAR1, can act as a volume transmitter that linked neuronal activity, cerebral blood flow, energy metabolism, and energy substrate availability.

3. Wagner W., et al. L- and D-lactate enhance DNA repair and modulate the resistance of cervical carcinoma cells to anticancer drugs via histone deacetylase inhibition and hydroxycarboxylic acid receptor 1 activation. Cell Communication & Signaling. 2015, 13(1): 36. PubMed ID: 26208712
   
   

   This study investigated the role of L- and D-lactate in the DNA damage response in cervical cancer cells. The findings suggested that the L- and D-lactate might be implicated in the modulation of cellular DNA damage repair process and in the resistance to anticancer therapy in cervical carcinoma cells.

4. Liu C., et al. 3, 5-Dihydroxybenzoic acid, a specific agonist for hydroxycarboxylic acid 1, inhibits lipolysis in adipocytes. Journal of Pharmacology & Experimental Therapeutics. 2012, 341(3): 794-801. PubMed ID: 22434674
   
   

   This article reported the identification of a specific agonist for HCAR1, 3, 5-dihydroxybenzoic acid (3, 5-DHBA). This agonist was useful for the in vivo study of HCAR1 function and it laid the foundation for further HCAR1 agonist design.

5. Wagner W., et al. Stimulation of lactate receptor (HCAR1) affects cellular DNA repair capacity. DNA Repair. 2017, 52: 49-58. PubMed ID: 28258841
   
   

   This study examined the possible mechanisms of HCAR1-mediated enhancement of DNA repair capacity using HCAR1 agonists and HCAR1 silencing tools.

HCAR1 Preparation Options

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Reference

1. Ahmed K. (2011). Biological roles and therapeutic potential of Hydroxy-carboxylic acid receptors. Frontiers in Endocrinology. 2: 51.

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