The systematic SAR study of a "caging" group showed a strong influence of the position of the donor dimethylamino group on the efficiency of photolysis of the DMAQ (2-hydroxymethylene-(N,N-dimethylamino)quinoline) caged acetate under one-photon near-UV or two-photon near-IR excitation. Photorelease of l-glutamate by the most efficient 8-DMAQ derivative strongly and efficiently activated glutamate receptors, generating large, fast rising responses similar to those elicited by glutamate photoreleased from the widely used MNI-caged glutamate.

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After opening, the Shaker voltage-gated potassium (K V ) channel rapidly inactivates when one of its four N-termini enters and occludes the channel pore. Although it is known that the tip of the N-terminus reaches deep into the central cavity, the conformation adopted by this domain during inactivation and the nature of its interactions with the rest of the channel remain unclear. Here, we use molecular dynamics simulations coupled with electrophysiology experiments to reveal the atomic-scale mechanisms of inactivation. We find that the first six amino acids of the N-terminus spontaneously enter the central cavity in an extended conformation, establishing hydrophobic contacts with residues lining the pore. A second portion of the N-terminus, consisting of a long 24 amino acid a-helix, forms numerous polar contacts with residues in the intracellular entryway of the T1 domain. Double mutant cycle analysis revealed a strong relationship between predicted interatomic distances and empirically observed thermodynamic coupling, establishing a plausible model of the transition of K V channels to the inactivated state.