Based on the composition of the five subunits
forming functional neuronal nicotinic acetylcholine receptors (nAChRs), they are grouped into either heteromeric (comprising both α and β subunits) or homomeric (comprising only α subunits) receptors. The nAChRs are known to be differentially
permeable to calcium ions, with the α7 nAChR subtype
having one of the highest permeabilities to
calcium. Calcium influx through nAChRs, particularly through the α-bungarotoxin-sensitive
α7-containing nAChRs, is a very efficient way to
raise cytoplasmic calcium levels. The activation of nAChRs can mediate three types of cytoplasmic calcium
signals: (1) direct calcium influx through the nAChRs,
(2) indirect calcium influx through voltage-dependent calcium channels (VDCCs) which are activated by the nAChR-mediated
depolarization, and (3) calcium-induced calcium release (CICR) (triggered by
the first two sources) from the endoplasmic reticulum (ER) through the ryanodine receptors and inositol (1,4,5)-triphosphate receptors (IP3Rs). Downstream signaling events mediated by nAChR-mediated
calcium responses can be grouped into instantaneous effects (such as
neurotransmitter release, which can occur in milliseconds after nAChR activation), short-term effects (such as the recovery
of nAChR desensitization through cellular signaling
cascades), and long-term effects (such as neuroprotection via gene expression). In addition, nAChR activity can be regulated by cytoplasmic calcium levels, suggesting a complex reciprocal relationship. Further advances in imaging techniques,
animal models, and more potent and subtype-selective ligands for neuronal nAChRs would help in understanding the
neuronal nAChR-mediated calcium signaling, and lead
to the development of improved therapeutic treatments.
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