Acetylcholine hyperpolarizes central neurones by acting on an M₂ muscarinic receptor

Abstract

Acetylcholine (ACh) is considered to act as a neurotransmitter in the mammalian brain by binding to membrane receptors and bringing about a change in neurone excitability. In the case of muscarinic receptors, cell excitability is usually increased¹; this effect results from a closure of membrane potassium channels in cortical cells^2,3. However, some central neurones are inhibited by ACh¹, and we hypothesized that these two opposite effects of ACh resulted from interactions with different subtypes of muscarinic receptor. We made intracellular recordings from neurones in the rat nucleus parabrachialis, a group of neurones in the upper pons some of which themselves synthesize ACh^4,5. ACh and muscarine caused a membrane hyperpolarization which resulted from an increase in the membrane conductance to potassium ions. The muscarinic receptor subtype was characterized by determining the dissociation equilibrium constant (K_D) for pirenzepine during the intracellular recording; the value of ∼600 nM indicates a receptor in the M₂ class. This muscarinic receptor is quite different from that which brings about a decrease in potassium conductance in other neurones, which has a pirenzepine K_D of ∼10nM (M₁ receptors)^6–8. It is possible that antagonists selective for this kind of M₂ receptor would be useful in the management of conditions, such as Alzheimer's disease, which are associated with a reduced effectiveness of cholinergic neurones.