GABA_B Receptor Complex as a Potential Target for Tumor Therapy

Abstract

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the vertebrate central nervous system. Metabotropic GABAB receptors are heterodimeric G-protein-coupled receptors (GPCRs) consisting of GABAB1 and GABAB2 subunits. The intracellular C-terminal domains of GABAB receptors are involved in heterodimerization, oligomerization, and association with other proteins, which results in a large receptor complex. Multiple splice variants of the GABAB1 subunit have been identified in which GABAB1a and GABAB1b are the most abundant isoforms in the nervous system. Isoforms GABAB1c through GABAB1n are minor isoforms and are detectable only at mRNA levels. Some of the minor isoforms have been detected in peripheral tissues and encode putative soluble proteins with C-terminal truncations. Interestingly, increased expression of GABAB receptors has been detected in several human cancer cells and tissues. Moreover, GABAB receptor agonist baclofen inhibited tumor growth in rat models. GABAB receptor activation not only induces suppressing the proliferation and migration of various human tumor cells but also results in inactivation of CREB (cAMP-responsive element binding protein) and ERK in tumor cells. Their structural complexity makes it possible to disrupt the functions of GABAB receptors in various ways, raising GABAB receptor diversity as a potential therapeutic target in some human cancers.

A miRNAs panel promotes the proliferation and invasion of colorectal cancer cells by targeting GABBR1

“…GABB receptors have been the important targets of` neurological diseases' treatment. Additionally, recent studies showed that GABB receptor also has been the potential target for tumor therapy 38. GABB receptor has been detected in human hepatocellular carcinoma (HCC) cells.…”

GABABR/GSK‐3β/NF‐κB signaling pathway regulates the proliferation of colorectal cancer cells

“…Colorectal cancer (CRC) is a major cause of cancer mortality worldwide with approximately 694,000 recorded deaths from the disease in 2012 . It is estimated that more than 1 million cases are diagnosed annually and around 600,000 of them are death .…”

Role of ESR Pathway Genes in Breast Cancer: A Review

“…increasing number of studies have demonstrated the potential roles of the neurotransmitter receptor GABAB as tumor suppressors in various cancers [20]. For instance, in colorectal cancer, upregulation of GABAB significantly inhibits the growth of the tumor by halting cell proliferation [21].…”

“…One report observes that GABAB 1 expression was significantly higher in malignant tissues than in nonmalignant tissues in ductal breast cancer [23]. Unfortunately, this observation is hardly reliable since this was only observed in 3 out of 6 samples, and consequently to have more accurate and reliable analyses, it is pertinent to study GABAB in more breast cancer samples.…”