Cholinergic receptors: functional role of nicotinic ACh receptors in brain circuits and disease

Abstract

The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability throughout the nervous system by acting on both the cys-loop ligand-gated nicotinic ACh receptor channels (nAChRs) and the G protein-coupled muscarinic ACh receptors (mAChRs). The hippocampus is an important area in the brain for learning and memory, where both nAChRs and mAChRs are expressed. The primary cholinergic input to the hippocampus arises from the medial septum and diagonal band of Broca, the activation of which can activate both nAChRs and mAChRs in the hippocampus and regulate synaptic communication and induce oscillations that are thought to be important for cognitive function. Dysfunction in the hippocampal cholinergic system has been linked with cognitive deficits and a variety of neurological disorders and diseases, including Alzheimer's disease and schizophrenia. My lab has focused on the role of the nAChRs in regulating hippocampal function, from understanding the expression and functional properties of the various subtypes of nAChRs, and what role these receptors may be playing in regulating synaptic plasticity. Here, I will briefly review this work, and where we are going in our attempts to further understand the role of these receptors in learning and memory, as well as in disease and neuroprotection.

Fig. 1

Molecular model of the rat α7 nAChR with ligand-binding domain. A side view of the pentameric α7 receptor model is shown on the left. The α-helices are shown in red and the β-strands in blue. The extracellular ligand-binding domain is shown up close on the right. The ligand-binding site is composed of a cluster of aromatic residues from both the principal and complementary subunits and is capped by the C-loop. The transition domain consists of several loops as shown

Fig. 2

The rate of α7 nAChR desensitization is altered by mutagenesis. Inward current responses (left) due to the rapid application of ACh for wild-type (left) and W55A mutant α7 receptor (right) expressed in Xenopus oocytes. Close up of the ligand-binding domain highlighting residues W55 and P180