Engineering the Ligand Selectively of Ion Channels

1 Resistance Mutations in L-type Calcium Channel Signaling 

For kinases and GTPases, point mutations can be used to study one member of a large family by allowing the engineered member to bind to a unique 

It has been proposed that capsaicin serves chili peppers by selectively deterring predators. Birds, productive vectors for seed dispersion, do not respond to capsaicin. In contrast, mammals are predatory but are deterred by the capsaicin (with the exception of humans) [26], The molecular basis of the differential capsaicin sensitivity between birds and mammals can be traced to VR1 [27]. The avian homolog of VR1, like its mammalian counterpart, is responsive to heat but unlike its mammalian counterpart, avian VR1 does not respond to capsaicin. 

Perhaps more remarkable than the ability to use the differences between chick (insensitive) and rat (sensitive) to construct a mutant insensitive rat VR1, was the use of the rat receptor to guide the construction of a capsaicin-sensitive chick receptor. Building the binding pocket required more than a point mutation the active construct borrowed 45 amino acids from the rVRl inserted into the correct position in the cVRl. Essentially, the molecular basis of this selective deterrence causing birds, but not mammals, to consume chili peppers is explained by a biochemical change in ligand specificity, induced by a few amino acids in mammal versus avian VR1. 

Wild type Reference state Control for the off-target effects of the ligand 

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