Clathrin regulates the β-arrestin pathway regardless of ligand bias

μ-opioid receptors (MOP) are thought to activate the G protein-mediated analgesic pathway and β-arrestin 2-mediated side effect pathway; however, ligands that recruit β-arrestin 2 only minimally to MOP may also cause opioid side effects. Such side effects are also induced in mutant mice lacking β-arrestin 2 or expressing phosphorylation-deficient MOP that do not recruit β-arrestin 2. These findings critically questioned whether β-arrestin 2 recruitment to MOP triggers side effects. Here, we show that β-arrestin 1 partially compensates for the lack of β-arrestin 2 in a neuronal cell line and thus might be involved in triggering such side effects in β-arrestin 2-null mice. Moreover, the magnitude of β-arrestin-mediated signals is not correlated with β-arrestin recruitment to MOP via phosphorylation of the carboxyl-terminal of MOP, which has long been used to evaluate β-arrestin bias of a ligand. Instead, β-arrestin activates downstream signals by binding with the clathrin heavy chain in the process of clathrin-coated pit formation. Our findings provide not only a novel insight into G protein-coupled receptor-mediated signalling to overcome opioid side effects but also an unexpected concept that the accumulation of molecules required for endocytosis is a key for activating the intracellular signalling.

The characteristic response of domestic cats to plant iridoids allows them to gain chemical defense against mosquitoes

Domestic cats and other felids rub their faces and heads against catnip (Nepeta cataria) and silver vine (Actinidia polygama) and roll on the ground as a characteristic response. While this response is well known, its biological function and underlying mechanism remain undetermined. Here, we uncover the neurophysiological mechanism and functional outcome of this feline response. We found that the iridoid nepetalactol is the major component of silver vine that elicits this potent response in cats and other felids. Nepetalactol increased plasma β-endorphin levels in cats, while pharmacological inhibition of μ-opioid receptors suppressed the classic rubbing response. Rubbing behavior transfers nepetalactol onto the faces and heads of respondents where it repels the mosquito, Aedes albopictus. Thus, self-anointing behavior helps to protect cats against mosquito bites. The characteristic response of cats to nepetalactol via the μ-opioid system provides an important example of chemical pest defense using plant metabolites in nonhuman mammals.

Modulating β-Arrestin-2 Recruitment at the δ- and μ-Opioid Receptors Using Peptidomimetic Ligands

µ Opioid receptors agonists provide potent and effective acute analgesia; however, their therapeutic window narrows considerably upon repeated administration, such as required for treating chronic pain. In contrast, bifunctional µ/δ...

Exploring μ-Opioid Receptor Splice Variants as a Specific Molecular Target for New Analgesics

Since a μ-opioid receptor gene containing multiple exons has been identified, the variety of splice variants for μ-opioid receptors have been reported in various species. Amidino-TAPA and IBNtxA have been discovered as new analgesics with different pharmacological profiles from morphine. These new analgesics show a very potent analgesic effect but do not have dependence liability. Interestingly, these analgesics show the selectivity to the morphine-insensitive μ-opioid receptor splice variants. The splice variants, sensitive to these new analgesics but insensitive to morphine, may be a better molecular target to develop the analgesics without side effects.