Agonism and antagonism in cyclic nucleotide-gated channels

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Cells control their life processes by producing natural chemical compounds (messengers) that bind to specific receptor proteins; in response, the receptors change their molecular structure in order to activate a particular biological function. Many physiological disorders, such as cancer and heart disease which afflict millions of Canadians, could be fought by artificial messengers (drugs) that either stimulate or suppress the ON- and OFF-switching of a specific receptor. My lab studies certain receptors called ion channels whose ON-conformation produces an electric current, so we can observe ON- and OFF-switching directly. We study a number of different ion channels, all of which respond to one type of messenger called cyclic nucleotide; this messenger is generated by the body under conditions of excitation, such as the "fight-or-flight" adrenaline rush, or during epileptic seizures in some parts of the brain. The molecules that form these ion channels all contain a specific sensing-domain which is the site for binding cyclic nucleotide. This sensing-domain obviously helps ON-switching after cyclic nucleotide is bound, but our lab has discovered that in different kinds of channels, the sensing-domain can do much more! For instance, in some channels, the sensing-domain will push the receptor OFF after being ON. These separate mechanisms reflect slight differences between the sensing-domains in different channels. We are finding what these key structural differences are: we change the ion channel's structure in a specific location ourselves by genetic engineering, and watch which of the different mechanisms are changed in consequence. In another strategy, certain chemical compounds bind the channel but their binding requires a very specific channel structure; we can thus use these compounds to test if that structure is present or absent in each of the separate mechanisms. We will thus learn how the basic blueprint for the sensing-domain can be modified in some details to produce very new actions. This will create a foundation of knowledge for engineering new actions in new versions of the sensing-domain.