ABSTRACT
Covering: 1860-2016A mechanistic link may exist between convulsant plant substances typified by picrotoxinin, and 'neurotrophic' sesquiterpenes like jiadifenolide. Picrotoxinin elicits convulsion by anion blockade of the Cys-loop family of neurotransmitter-gated ion channels. These same receptors mediate neuronal development and neurite outgrowth prior to synapse formation. Due to its structural homology with picrotoxin and anisatin, it is possible that jiadifenolide enhances NGF-stimulated neurite outgrowth by modulation of the Cys-loop family of receptors.
Subject(s)
Convulsants/pharmacology , Neurites/drug effects , Sesquiterpenes/pharmacology , Convulsants/chemistry , Lactones/chemistry , Lactones/pharmacology , Molecular Structure , Picrotoxin/analogs & derivatives , Picrotoxin/chemistry , Picrotoxin/pharmacology , Sesquiterpenes/chemistry , Sesterterpenes , Spiro Compounds/chemistry , Spiro Compounds/pharmacologyABSTRACT
Proteins within the EF-hand protein family exhibit different conformational responses to Ca(2+) binding. Calmodulin and other members of the EF-hand protein family undergo major changes in conformation upon binding Ca(2+). However, some EF-hand proteins, such as calbindin D9k (Clb), bind Ca(2+) without a significant change in conformation. Here, we investigate the effects of replacement of a leucine at position 39 of the N-terminal domain of calmodulin (N-Cam) with a phenylalanine derived from Clb. This variant is studied alone and in the context of other mutations that affect the conformational properties of N-Cam. Strikingly, the introduction of Phe39, which is distant from the calcium binding sites, leads to a significant enhancement of Ca(2+) binding affinity, even in the context of other mutations which trap the protein in the closed form. The results yield novel insights into the evolution of EF-hand proteins as calcium sensors versus calcium buffers.
