A couple of recent news posts on the Pain Research Forum that caught my eye with their links to the flora and fauna of this land Down Under.
A cell-penetrating peptide from the venom of the Australian black rock scorpion activates TRPA1 to cause pain but not neurogenic inflammation.
Transient receptor potential ankyrin 1 (TRPA1) is an ion channel expressed by many primary afferent sensory neurons. Allyl isothiocyanate (AITC), a pungent chemical that gives wasabi and mustard oil their powerful taste, is a well-known activator of the channel, as are substances produced by many other plants. In addition, a host of animals produce chemical irritants in their venoms that activate TRP channels in order to ward off predators. Now, a newly discovered and unique toxin from the venom of a scorpion is further illuminating the workings of TRPA1.
Research led by David Julius, University of California, San Francisco, US, along with first author John Lin King, a graduate student in neuroscience, and colleagues now identifies a peptide toxin from the venom of the Australian black rock scorpion (Urodacus manicatus) that modulates TRPA1 function. It does so by penetrating the plasma membrane and binding to the channel intracellularly, to prolong channel opening. Interestingly, this toxin elicits pain hypersensitivity without the typical accompanying neurogenic inflammation seen with other TRPA1 activators.
“[T]he work done by [the researchers] in identifying a new natural ligand of TRPA1 that stabilizes a unique channel conformation offers scientists both a new tool to probe TRPA1 receptor function and potential strategies for the future development of novel analgesics,” wrote Dustin Green and Xinzhong Dong, Johns Hopkins University School of Medicine, Baltimore, US, in an accompanying preview.
Major efforts are underway to develop new opioid drugs that relieve pain without dangerous adverse effects. One strategy relies on biased agonism—a term that describes preferential activation of one downstream signaling pathway over another upon binding of an agonist to a receptor. In the case of mu-opioid receptor (MOR) agonists, researchers are seeking compounds that activate pathways responsible for analgesia while avoiding pathways that mediate negative outcomes like respiratory depression and tolerance.
Now, a peptide isolated from a fungus found in an extremely remote place in the world seems to activate MOR with biased agonism, favoring G protein signaling, thought to underlie analgesia, while avoiding beta-arrestin signaling, which regulates multiple adverse effects of opioids, according to previous studies. The peptide contained just four amino acids in a never-before-seen structure that fit perfectly into the MOR binding pocket…
… the researchers found the new peptides by screening extracts from the fungus Penicillium sp. MST-MF667, which they discovered in a pristine Tasmanian estuary. Whereas “99.999 percent of amino acids in the world are left-handed,” said Christie, these peptides contained right-handed, mirror-image amino acids. “This structure had never been seen before,”…
As unusual as the structure was, co-first author Zoltan Dekan, University of Queensland, Australia, noticed that the peptides bore an uncanny resemblance to mammalian endogenous opioid peptides. (Indeed, the bilaids bound the human MOR with modest affinity, Christie told PRF. “Then we made some modifications, in ways well understood to increase potency, and got a 1,000-fold increase in potency and selectivity” with a compound they called bilorphin…
Both pieces provide relevant and useful background information that will add to your molecular biology knowledge base and are well worth reading in full.
Fair warning though, the more you read in the the basic science and molecular biology literature, the more you will question simplistic and trivial explanations of transduction, nociception, and pain!!