4.5 Review

Dynorphin 1-17 biotransformation peptides: properties, challenges and solutions for future therapeutics development

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Summary: Modulation of corticostriatal plasticity is crucial for motor learning, action selection, and reward. Two distinct networks of GPCR signaling cascades regulate synaptic plasticity in the striatal direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs). This study reveals that dynorphin, through Kappa Opioid Receptor (KOR) signaling, selectively suppresses long-term potentiation (LTP) in dSPNs, counterbalancing with D1 receptor activation. Mice lacking dynorphin in D1 neurons show enhanced flexibility during reversal learning, suggesting bi-directional modulation of synaptic plasticity and behavior in the direct pathway.

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Summary: Dynorphins are endogenous neuropeptides that act as ligands for the j-opioid receptor. They can induce pathological effects and previous research has shown that Dynorphin A (DynA) can form transient pores in lipid domains of the plasma membrane. This study demonstrates that DynA induces pore formation in negatively charged membranes, and computational simulations support the stability of peptide arrangements in the hydrophobic core of the bilayer. The findings suggest that DynA is capable of assembling in charged membranes to form water-filled pores that conduct ions.

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Summary: Kappa opioid receptor (KOR) antagonists, such as the newly synthesized cyclized analogs, have shown promising potential in treating drug addiction and mood disorders by stabilizing bioactive conformation and enhancing metabolic stability. This cyclization strategy provides novel leads for further exploration of KOR pharmacology.

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