Abstract:
:Guanidine and its alkyl analogs stimulate the neuromuscular junction presynaptically by inhibiting voltage-gated potassium (Kv) channels, leading to enhanced release of acetylcholine in the synaptic cleft. This stimulatory effect of guanidine underlies its use in the therapy for the neuromuscular diseases myasthenic syndrome of Lambert-Eaton and botulism. The therapeutic use of guanidine is limited, however, because of side effects that accompany its administration. Therefore, the design of guanidine analogs with improved therapeutic indices is desirable. Progress toward this goal is hindered by the lack of knowledge of the mechanism by which these molecules inhibit Kv channels. Here we examine an array of possible mechanisms, including charge screening, disruption of the protein-lipid interfaces, direct interaction with the voltage sensors, and pore-binding. Our results demonstrate that guanidines bind within the intracellular pore of the channel and perturb a hydrophobic subunit interface to stabilize a closed state of the channel. This mechanism provides a foundation for the design of guanidine analogs for the therapeutic intervention of neuromuscular diseases.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Kalia J,Swartz KJdoi
10.1124/mol.111.074989subject
Has Abstractpub_date
2011-12-01 00:00:00pages
1085-95issue
6eissn
0026-895Xissn
1521-0111pii
mol.111.074989journal_volume
80pub_type
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