Data Tracking Can Help Collate Mas-related G Protein Receptor Research

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research into the g protein receptors
A g-protein coupled receptor. Source: Wikipedia user Opabinia regalis.

It’s no secret that G protein receptors are among the most important classes of receptors. Neuroscientists, systems biologists and cellular biologists all know the critical importance of G protein coupled receptors in activating signalling pathways, yet few have the idea to investigate these receptors for their impact on pain.1 A new review examining the available literature on Mas-related G protein coupled receptors (MRGPRs) exhorts other cellular biologists and neuroscientists to investigate them as potential targets for pain relief.2 Mas-related GPCRs exist only in sensory neurons, and are implicated in itching and nociception. As the review notes, even though dozens of these MRGPRs have been characterized and exploited for use in a wide variety of different drug therapies, there are still potentially thousands remaining which aren’t understood. Some of the MRGPR subfamilies don’t even have a known ligand—a testament to their mysteriousness.3

In these unknown receptors, a unique approach to reducing pain may be hiding. To understand these MRGPRs and develop analgesics based off of their operation, researchers will need powerful data tracking and collaboration software that will organize their efforts as they explore the vast field of unknown receptors.

What Makes Mas-Related Receptors Special?

MRGPRs get their name from the Mas amino acid sequence that differentiates them from the larger family of G protein coupled receptors. The Mas amino acid sequence was notable when discovered due to its status as one of the first characterized oncogenes—MAS1—but its functions are far broader than initially thought.4 Thus the entire family of proteins was named after their relationship to MAS1, leading to the MRGPR nomenclature of today.

The review claims that MRGPRs are worthwhile targets of investigation independent of their effect on pain due to their ability to attenuate neuronal activity and their signalling complexity. Rather than simply activating or inhibiting neuronal action potentials when ligated, MRGPRs can activate, inhibit, modulate sensitivity, pause or alter the response of neurons and their genes depending on the ligand. Given that some of these actions require cofactors or certain genetic conditions to occur, researchers of the future will have an extremely powerful and versatile toolbox if they can crack the functionality of a single MRGPR.

Astoundingly, and unlike most receptors, MRGPRs could also be used as a non-subjective assay in and of themselves to quantify pain persistence after an injury. Researchers or doctors could assay the transcription of a pain associated MRGPR to see whether a patient’s pain would be likely to increase or decrease in the near future. The authors of the review point to several experiments of this type in mice, praising the new line of inquiry.

Finding a Novel Pain Pathway

The appeal of MRGPRs specifically in analgesia is a bit more convoluted than in a simple assay of pain. Though the basis of nociception is understood, many of the finer points regarding sensory neuron propagation of pain resulting from Mas-related G protein receptor ligation are unclear.5 6 Researchers will need to harvest a boatload of data to clarify the situation if they’re interested in making a therapy based on MRGPRs.

According to the review’s synthesis of published research, in sensory neurons MRGPRs are bound by endogenously produced ligands which modulate pain. These same endogenous ligands bind to canonical pain related receptors like the opioid receptor family. Importantly, MRGPRs don’t bind to other endogenous or artificially introduced opioid receptor ligands, nor are they affected by opioid receptor antagonists.

This means that while MRGPRs may share a role in pain reduction that has points of overlap with the opioid pathway, a drug targeting MRGPRs for pain relief could probably avoid some of the negative consequences of opioid receptor ligands such as respiratory depression, mental sluggishness and addiction.7 It would also give an analgesic drug targeting MRGPR the ability to treat pain in cases of opioid overdose treatment, which involves opioid antagonists.8 There’s a million potential niches for drugs targeting MRGPR, but researchers have a lot of leg work to do before a drug can reach the in vivo testing, nevermind the clinic.

Surveying the Field in the Future

To characterize new MRGPRs, researchers will have to put in a lot of hours hunting down signalling pathways, protein structures, gene regulation pathways, and downstream nociception. For each new receptor, researchers will need to:

  • Identify the MRGPR’s subfamily and its type of nociception
  • Quantify the prevalence of the new MRGPR in canonical sensory neuron strata
  • Quantify the prevalence of the new MRGPR in all other sensory neuron strata
  • Determine whether the new MRGPR uses a canonical signaling pathway or has a unique signaling pathway
  • Characterize the new MRGPR’s new signaling pathway and all of its constituent parts
  • Determine whether the new MRGPR uses a canonical ligand, a novel ligand, or multiple ligands
  • Determine whether each of the new MRGPR’s ligands activate its signaling pathways equally or whether they activate a different pathway altogether
  • Determine whether the new MRGPR’s ligands are endogenously produced as a result of a genetic self-regulation mechanism which the MRGPR’s signaling pathway influences
  • Determine the gene regulation profile of the new MRGPR
  • Crystallize the new MRGPR or calculate its protein structure along with all of its ligands
  • Determine whether the perceived downstream effects of MRGPR ligation are suitable for analgesia or whether they are subjectively intolerable to research subjects

There’s enough work in each MRGPR investigation to keep several laboratories busy for years. It’s important to remember that there are at minimum hundreds of MRGPRs left to characterize, and it’s extremely likely that more than a few will need to be characterized before researchers can find a useful drug target. Tracking all of this data won’t be easy, but thankfully there’s a new information management suite that can make drug development with MRGPRs much easier.

ONE Lab is the information management and data tracking solution which your lab can use to dive into the rich world of MRGPRs. Using ONE Lab, managing the planning, analysis, execution, and iteration of sequences of experiments will go off without a hitch. Contact us today to find out how we can help you break open the field of MRGPR targeted analgesics and revolutionize pain therapy.

  1.  “Activation of Molecular Switches in GPCRs – Theoretical and Experimental Studies.” March 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343417/
  2. “Mas-Related G Protein-Coupled Receptors Offer Potential New Targets for Pain Therapy.” May 2016, https://www.researchgate.net/publication/301646854_Mas-Related_G_Protein-Coupled_Receptors_Offer_Potential_New_Targets_for_Pain_Therapy
  3. “Membrane-Delimited Coupling of TRPV1 and mGluR5 on Presynaptic Terminals of Nociceptive Neurons.” August 2009, http://www.jneurosci.org/content/29/32/10000.full?cited-by=yes;29/32/10000
  4. “Isolation and Characterization of a New Cellular Oncogene Encoding A Protein With Multiple Potential Transmembrane Domains.” June 1986, http://www.cell.com/cell/pdf/0092-8674(86)90785-3.pdf?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2F0092867486907853%3Fshowall%3Dtrue
  5. “Cellular and Molecular Mechanisms of Pain.” October 2009, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852643
  6. “Nociceptors– Noxious Stimulus Detectors.” August 2007, https://www.ncbi.nlm.nih.gov/pubmed/17678850
  7. “Unidirectional Cross-activation of GRPR by MOR1D Uncouples Itch and Analgesia Induced by Opioids.” October 2014, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197217/
  8. “Naloxone Hydrochloride.” https://www.drugs.com/monograph/naloxone-hydrochloride.html