Background: Mambalgin-2 is a snake venom peptide that blocks acid-sensing ion channels (ASICs) to relieve pain. Results: Mambalgin-2 interacts with at least three different regions of ASICs and exerts both stimulatory and inhibitory effects. Conclusion: Binding of mambalgin-2 into the pH sensor traps the channels in the closed conformation. Significance: This might allow development of optimized blockers of ASICs of therapeutic value.

Mambalgins are peptides isolated from mamba venom that specifically inhibit a set of acid-sensing ion channels (ASICs) to relieve pain. We show here the first full stepwise solid phase peptide synthesis of mambalgin-1 and confirm the biological activity of the synthetic toxin both in vitro and in vivo. We also report the determination of its three-dimensional crystal structure showing differences with previously described NMR structures. Finally, the functional domain by which the toxin inhibits ASIC1a channels was identified in its loop II and more precisely in the face containing Phe-27, Leu-32, and Leu-34 residues. Moreover, proximity between Leu-32 in mambalgin-1 and Phe-350 in rASIC1a was proposed from double mutant cycle analysis. These data provide information on the structure and on the pharmacophore for ASIC channel inhibition by mambalgins that could have therapeutic value against pain and probably other neurological disorders.

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Introduction: Nerve ultrasound has been used increasingly in clinical practice as a complementary test for diagnostic assessment of neuropathies, but nerve biopsy remains invaluable in certain cases. The aim of this study was to compare ultra-high-frequency ultrasound (UHF-US) to histologic findings in progressive polyneuropathies. Methods: Ten patients with severe, progressive neuropathies underwent ultrasound evaluation of the sural nerve before nerve biopsy. Ultrasound data were compared with histologic results in a retrospective manner. Results: Sural nerves were easily identified on UHF-US. Nerve hyperechogenicity correlated with inflammatory infiltrates on biopsy. Nerve fascicles could be identified and measured on ultrasound in the majority of patients. Discussion: Hyperechogenicity on UHF-US may be a marker of nerve inflammation in neuropathies. Furthermore, the UHF-US probe allows for evaluation of sensory nerves in spite of their small size, providing valuable information on their size and on their internal structure.

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