Thanks role in human cardiac tissue. Haga et

Thanks to advances in x-ray crystallography and more powerful computing
resources, the intricate study of the three-dimensional conformations (i.e. the
shapes) of organic macromolecules is now possible. It is well understood that acetylcholine
acts on two discrete types of receptors: ionotropic and metabotropic. The two
types of ACh receptors are named according to their primary
neuropharmacological agonist: the pentameric nicotinic (for nicotine) receptors
(nAChRs) and muscarinic (for muscarine) receptors (mAChRs). Nicotinic ACh
receptors are ionotropic and muscarinic receptor are metabotropic. Ionotropic
receptors act as ligand-gated ion channels (i.e. regulating the conductance of
ions across the plasma membrane) and metabotropic receptors act as ligand-gated
G protein coupled receptors (GPCRs). Metabotropic receptors are particularly interesting
due to their diversity, complex signaling pathways, and the types of unique
responses that they can illicit. The first human acetylcholine receptor to be
structurally characterized was the M2 muscarinic (metabotropic) receptor by Haga
et al. (2011). The M2 ACh receptor
has significant pharmacological interest due to its essential role in human cardiac
tissue. Haga et al. characterized the
orthosteric (primary) and several allosteric binding sites of the M2 mAChR (2011).
Allosteric binding sites are distinct from the orthosteric site. Although the
five mAChRs (M1-M5) share significant sequential genetic homology, they exhibit
unique and vastly different physiological responses. The structural homology of
mAChRs has led to significant difficulties in the designing of therapeutic
agents with distinct subtype biases. Building upon the work by Haga et al. (2011), Kruse et al. have characterized the structure
of the M3 mAChR (in rats) and identified the orthosteric and allosteric binding
sites (2011). The ability to specifically target mAChRs can potentially have
direct clinical implications in medicine.


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