Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus
Section snippets
Muscarinic receptor expression in the brain
The diversity of mAChR subtypes and signaling pathways indicates that the localization of each receptor dictates the potential muscarinic responses to ACh in various cell types. Thus, considerable effort has been made to map the distribution of the mAChRs using a variety of approaches to detect each receptor. Many ligand autoradiographic binding studies have yielded insights into the relative abundance of the mAChR subtypes in brain (Cortes and Palacios, 1986, Mash and Potter, 1986, Spencer et
M1 is the major postsynaptic mAChR in the hippocampus
mAChRs expressed in the hippocampus, play a role in learning and memory (Jerusalinsky et al., 1997), and degeneration of cholinergic projections to the hippocampus has been implicated in Alzheimer's disease (Bartus et al., 1982, Gallagher and Colombo, 1995). Therefore, much research has focused on identifying the cellular mechanisms by which mAChR activation might contribute to learning and memory. One of the effects of mAChR activation in the hippocampus is potentiation of current through the
mAChR trafficking following acute stimulation
Following agonist stimulation, GPCRs undergo desensitization mediated by phosphorylation and binding of arrestin (Lefkowitz, 1998). In addition to preventing receptor interaction with the G protein, arrestin facilitates the binding of clathrin which induces receptor internalization via clathrin coated vesicles. The internalized receptors then traffic to early endosomes in which an acidic pH is thought to mediate a conformational change in the receptor, allowing interaction with phosphatases and
Summary
The M1, M2 and M4 subtypes of mAChRs are the predominant receptors in the CNS. These receptors activate a multitude of signaling pathways important for modulating neuronal excitability, synaptic plasticity and feedback regulation of ACh release. In addition, novel functions mediated by mAChRs are currently being discovered. These studies are greatly facilitated by the recent development of subtype selective toxins and mice lacking individual mAChR genes.
Studies in cell culture and the rodent
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