Nicotinic acetylcholine receptor redux: Discovery of accessories opens therapeutic vistas

BACKGROUND

One hundred years ago, experiments on beating frog hearts identified acetylcholine (ACh) as the seminal neurotransmitter. Sixty years later, fractionation of the eel electroplax isolated nicotinic ACh receptors (nAChRs) as the first purified ion channel. We now appreciate that a family of nAChRs are differentially expressed in numerous tissues, including the brain, skeletal muscle, white blood cells, and cochlear hair cells. Paralleling this wide distribution, nAChRs mediate diverse physiological functions, including cognition, muscle contraction, immunomodulation, and sound discrimination. Neuronal nAChRs also account for the psychoactive and addictive properties of tobacco and are the primary genetic risk factors for lung cancer. Therapeutically, nAChRs provide pharmacological targets of approved medicines for cardiovascular and neurological disorders.

Nicotinic AChRs comprise multiple subunits whose molecular folding and surface trafficking involve complex and tightly regulated processes. As nAChRs often require tissue-specific factors for functional expression, many subtypes fail to create receptor channels in recombinant systems. Our limited understanding of nAChR assembly has impeded basic research and drug development.

ADVANCES

Studies in the 1970s found that smokers have increased nAChR density in the brain owing to receptor stabilization by nicotine—a process that likely contributes to tobacco addiction. Recent applications of proteomics, genetics, and expression cloning have identified a bevy of partner proteins and metabolites essential for nAChR function. These accessories act at multiple steps in nAChR biogenesis. Within the endoplasmic reticulum, chaperones mediate nAChR subunit folding and assembly. Other factors then promote nAChR trafficking to the plasma membrane. Finally, auxiliary subunits associated with surface nAChRs modulate channel activation. These chaperones and auxiliary subunits include both nAChR-specific regulators and more pleiotropic factors. On the one hand, NACHO (a neuronal endoplasmic reticulum–resident protein) serves as a client-specific chaperone for neuronal nAChRs. By contrast, transmembrane inner ear protein contributes to both hair cell nAChRs and mechanosensitive channels, which modulate cochlear amplification and transduce sound waves, respectively. Interplay between nAChR accessory components can further regulate receptor distribution and function.

OUTLOOK

Discovery of these molecules and mechanisms is transforming basic and translational science concerning nAChRs. Inclusion of appropriate chaperones during protein production is enabling structural studies of nAChR subtypes. Accessory components are also permitting biophysical studies of nAChR channel properties. Furthermore, understanding mechanisms that control trafficking and subunit composition is defining roles for nAChRs in biological processes and disease.

This research also provides therapeutic opportunities. The dearth of pharmacological agents for certain nAChRs results from challenges in recombinant expression of many receptor types. The ability to express complex nAChR subunit combinations in cell lines “unlocks” them for the chemical screening that initiates drug discovery. Auxiliary subunits can themselves provide pharmacological targets. Furthermore, drugging chaperone pathways may benefit myasthenia gravis and other diseases associated with aberrant nAChR levels.

Despite being the archetypal neurotransmitter receptor, much remains unknown about nAChRs. The identification of molecular partners and elucidation of regulatory mechanisms provide a cell biological renaissance and can suggest avenues for treating diseases associated with nAChR dysfunction.