AAV ACTOne Gi-GPCR Assay Kit-GRM8

Metabotropic Glutamate Receptor 8 (mGluR8 or GRM8) is a G protein-coupled receptor (GPCR) that belongs to the group III metabotropic glutamate receptors, which also includes mGluR4 and mGluR7. These receptors are activated by the neurotransmitter glutamate, which is the primary excitatory neurotransmitter in the central nervous system. Unlike ionotropic glutamate receptors that mediate rapid synaptic transmission, metabotropic receptors like GRM8 modulate neuronal activity and synaptic transmission through intracellular signaling pathways. GRM8 is primarily coupled with the Gi/Go class of G proteins, which inhibit adenylate cyclase, leading to a reduction in cyclic AMP (cAMP) levels. This decrease in cAMP results in the inhibition of neurotransmitter release, particularly glutamate, thereby modulating excitatory synaptic transmission. GRM8 is predominantly found in presynaptic terminals, where it acts as an autoreceptor, regulating the release of neurotransmitters in response to synaptic activity. Due to its involvement in modulating glutamate transmission, GRM8 has been implicated in several neurological and psychiatric disorders, including anxiety, epilepsy, schizophrenia, and neurodegenerative diseases. Research into GRM8 is ongoing, with a focus on developing therapeutic agents that target this receptor to treat conditions associated with dysregulated glutamate signaling.
This kit uses AAV vectors with a CMV promoter to co-express the GRM8 and cyclic nucleotide-gated (CNG) channel, allowing researchers to conduct high-throughput screening and functional analysis of potential GRM8-targeting compounds. The kit provides a sensitive and reliable method for evaluating the pharmacological properties of GRM8 drugs, such as agonists and antagonists, in a live-cell environment.

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Background

ACTOne™ is the only high-throughput GPCR screening technology that can directly measure the intracellular changes of the secondary messenger cyclic AMP (cAMP) in living cells, in real-time. It uses a proprietary modified cyclic nucleotide-gated (CNG) channel, which is co-localized with adenylate cyclase at the plasma membrane, as a biosensor of cAMP activity. The CNG channel opens when the cAMP level near the plasma membrane increases, resulting in ion flux and cell membrane depolarization. The influx of cations through the CNG channel can be quantified using fluorescent ion indicators or membrane potential (MP) dyes. It provides information on real time intracellular cAMP changes and is highly sensitive. By combining kinetic and endpoint readouts, we are able to capture and analyze transient responses from endogenous GPCRs and weak responses caused by weak Gs or Gi coupled GPCR activities. Using ACTOne, we are able to detect the subcellular cAMP concentration changes directly caused by GPCR activation. Real-time kinetic readouts minimize artifacts, and provide greater content and more statistically relevant data. The intensity of signal increase caused by GPCR activation is directly related to the receptor number on cell surface. Using ACTOne assay, we were able to detect activities of some endogenous Gs coupled receptors in HEK293 cells that have not been reported in literature. In addition, we have also detected weak Gs coupled activity of a GPCR that was widely considered to be only linked to Gq coupled pathway. The ACTOne assay also provides a useful tool for GPCR de-orphanization.