Plasma membrane poration by opioid neuropeptides: a possible mechanism of pathological signal transduction

Cell Death & Disease
O MaximyukO Krishtal

Abstract

Neuropeptides induce signal transduction across the plasma membrane by acting through cell-surface receptors. The dynorphins, endogenous ligands for opioid receptors, are an exception; they also produce non-receptor-mediated effects causing pain and neurodegeneration. To understand non-receptor mechanism(s), we examined interactions of dynorphins with plasma membrane. Using fluorescence correlation spectroscopy and patch-clamp electrophysiology, we demonstrate that dynorphins accumulate in the membrane and induce a continuum of transient increases in ionic conductance. This phenomenon is consistent with stochastic formation of giant (~2.7 nm estimated diameter) unstructured non-ion-selective membrane pores. The potency of dynorphins to porate the plasma membrane correlates with their pathogenic effects in cellular and animal models. Membrane poration by dynorphins may represent a mechanism of pathological signal transduction. Persistent neuronal excitation by this mechanism may lead to profound neuropathological alterations, including neurodegeneration and cell death.

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Citations

Mar 15, 2016·Immunotherapy·Sherise D FergusonAmy B Heimberger
Sep 24, 2016·Scientific Reports·Veronica AstroIvan de Curtis
May 4, 2017·Biopolymers·Anand A JoshiJane V Aldrich
Dec 2, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Joanna Starnowska-Sokół, Barbara Przewłocka
May 23, 2021·Experimental Brain Research·Georgy BakalkinHiroyuki Watanabe

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Methods Mentioned

BETA
fluorescence
FCS
fluorescence imaging
fluorescence correlation spectroscopy

Software Mentioned

OriginLab
PatchMaster
Origin
PharmaRobot
VassarStats

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