Download Orthosteric, allosteric and metabotropic activity of alpha7 nAChR

Orthosteric, allosteric, and metabotropic activity of alpha7 nAChR
Roger L. Papke1, Clare Stokes1, M. Imad Damaj2, Alain Simard3, Marta Quadri1,4, and
Nicole A. Horenstein4
1
Department of Pharmacology and Therapeutics, University of Florida, PO Box 100267
Gainesville, FL 32610-0267
2
Department of Pharmacology and Toxicology, Medical College of Virginia Campus,
Virginia Commonwealth University, Richmond, VA 23298-0613
3
Department of Chemistry and Biochemistry, University of Moncton, Moncton, Canada
E1A3E9
4
Department of Chemistry, University of Florida, PO Box 117200 Gainesville, FL 326117200
The  subtype of nAChR is a unique receptor, widely distributed throughout the brain
and expressed in many non-neuronal cells. These receptors function as
homopentamers, with five binding sites for orthosteric agonists. Although activatible by
acetylcholine (ACh) and the precursor molecule choline, orthosteric agonists produce
relatively little  channel activation compared to that produced with typical heteromeric
nAChR. This is, in part, because high levels of agonist binding induce forms of
desensitization that are unique to  receptors. The induction of these desensitized
states can be revealed with the use of efficacious positive allosteric modulators (PAMs)
such as PNU-120596. The use of PAMs have allowed us to identify a new class of
ligands, "silent agonists", which compete with orthosteric agonists but produce little or no
channel activation. Nonetheless, these silent agonists induce conformational changes
that include a desensitized state that can be converted to a conducting state by effects
of PAMs. The recent discovery of a cholinergic anti-inflammatory system associated
with  expression in cells of the immune system has expanded the therapeutic
indications for drugs targeting  receptors to encompass inflammatory diseases and
neuropathic pain. However, the cells that show -dependent regulation of inflammatory
cytokine production do not demonstrably have forms of the receptor that appear to be
capable of ion channel responses. Moreover, some of the ligands that are most
effective for regulating -sensitive inflammation are silent agonists like NS6740, which
induce very stable long-lived receptor desensitization. We have developed a new family
of silent agonists that are structural analogs of N,N-diethyl-N’-phenylpiperazine (DEPP).
Some of these DEPP-based silent agonists are very effective at reducing proinflammatory cytokine release in cell-based assays and are able to reduce neuropathic
and inflammation-related pain in mouse models. Additionally, the DEPP analogs show
promising effects in experimental autoimmune encephalomyelitis (EAE). These results
support the hypothesis that  receptors may, in addition to their ionotropic function that
can be enhanced by PAMs, have metabotropic activity that is produced by
conformational states associated with channel desensitization.