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

Maximyuk O, Khmyz V, Lindskog CJ, Vukojević V, Ivanova T, Bazov I, Hauser KF, Bakalkin G, Krishtal O - Cell Death Dis (2015)

Bottom Line: The dynorphins, endogenous ligands for opioid receptors, are an exception; they also produce non-receptor-mediated effects causing pain and neurodegeneration.The potency of dynorphins to porate the plasma membrane correlates with their pathogenic effects in cellular and animal models.Persistent neuronal excitation by this mechanism may lead to profound neuropathological alterations, including neurodegeneration and cell death.

View Article: PubMed Central - PubMed

Affiliation: State Key Lab for Molecular Biology, Bogomoletz Institute of Physiology, Kiev, Ukraine.

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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Activity of dynorphins is compared with the activity of synthetic nona-arginine (Arg9). (a) Representative recordings of membrane current noise measured in DRG neurons. (b) Summary results for scaling exponents α1vs α2 under different peptides show their activity profile. All data were obtained from DRG neurons clamped at −100 mV
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fig4: Activity of dynorphins is compared with the activity of synthetic nona-arginine (Arg9). (a) Representative recordings of membrane current noise measured in DRG neurons. (b) Summary results for scaling exponents α1vs α2 under different peptides show their activity profile. All data were obtained from DRG neurons clamped at −100 mV

Mentions: Recent studies have demonstrated that arginine-rich peptides generate negative Gaussian membrane curvature with the potency directly related to their arginine content.47, 48 We compared the potency of Dyn A, Dyn B, Big Dyn and nona-arginine (Arg9) to induce membrane current fluctuations (Figure 4). Application of 10 μM Dyn A (three arginines) induced clearly visible membrane current fluctuations and corresponding increases in the scaling exponent α1 from 0.79±0.09 to 1.14±0.22 (n=4; P<0.001) (Figure 4a), whereas equimolar concentration of Dyn B, which only contains two arginine residues, did not induce detectable changes in the current events and insignificantly affected self-similarity of membrane noise (α1=0.81±0.08; n=4; P=0.9997). Big Dyn (six arginines) induced most profound changes in the cellular membrane conductance as well as largest increase in the scaling exponent α1 (α1=1.25±0.17; n=15; P<0.0001), as summarized in Figure 4b. It should be noted that, contrary to all tested dynorphins, Arg9 affected both scaling exponents, α1 and α2, which may reflect a different mechanism of cell membrane perturbation as compared with dynorphins.


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

Maximyuk O, Khmyz V, Lindskog CJ, Vukojević V, Ivanova T, Bazov I, Hauser KF, Bakalkin G, Krishtal O - Cell Death Dis (2015)

Activity of dynorphins is compared with the activity of synthetic nona-arginine (Arg9). (a) Representative recordings of membrane current noise measured in DRG neurons. (b) Summary results for scaling exponents α1vs α2 under different peptides show their activity profile. All data were obtained from DRG neurons clamped at −100 mV
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4385918&req=5

fig4: Activity of dynorphins is compared with the activity of synthetic nona-arginine (Arg9). (a) Representative recordings of membrane current noise measured in DRG neurons. (b) Summary results for scaling exponents α1vs α2 under different peptides show their activity profile. All data were obtained from DRG neurons clamped at −100 mV
Mentions: Recent studies have demonstrated that arginine-rich peptides generate negative Gaussian membrane curvature with the potency directly related to their arginine content.47, 48 We compared the potency of Dyn A, Dyn B, Big Dyn and nona-arginine (Arg9) to induce membrane current fluctuations (Figure 4). Application of 10 μM Dyn A (three arginines) induced clearly visible membrane current fluctuations and corresponding increases in the scaling exponent α1 from 0.79±0.09 to 1.14±0.22 (n=4; P<0.001) (Figure 4a), whereas equimolar concentration of Dyn B, which only contains two arginine residues, did not induce detectable changes in the current events and insignificantly affected self-similarity of membrane noise (α1=0.81±0.08; n=4; P=0.9997). Big Dyn (six arginines) induced most profound changes in the cellular membrane conductance as well as largest increase in the scaling exponent α1 (α1=1.25±0.17; n=15; P<0.0001), as summarized in Figure 4b. It should be noted that, contrary to all tested dynorphins, Arg9 affected both scaling exponents, α1 and α2, which may reflect a different mechanism of cell membrane perturbation as compared with dynorphins.

Bottom Line: The dynorphins, endogenous ligands for opioid receptors, are an exception; they also produce non-receptor-mediated effects causing pain and neurodegeneration.The potency of dynorphins to porate the plasma membrane correlates with their pathogenic effects in cellular and animal models.Persistent neuronal excitation by this mechanism may lead to profound neuropathological alterations, including neurodegeneration and cell death.

View Article: PubMed Central - PubMed

Affiliation: State Key Lab for Molecular Biology, Bogomoletz Institute of Physiology, Kiev, Ukraine.

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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