The molecular basis of neurotransmission at the muscarinic receptor

Abstract

Neurotransmitters, hormones, and many drugs cause their effects by interacting specifically with their receptors. In most cases these receptors are highly specialized proteins on the outside surface of the cell. For agonists but not antagonists these interactions may induce conformational changes in the receptor molecule. These receptor changes induced by agonists may affect the electrical properties of cells by changing the membrane permeability, which ultimately leads to a biological response. The link between receptor activation and cellular response is mediated by various effecters. It has been hypothesized that receptors and effecters freely diffuse in the plane of the membrane and that coupling of the two takes place after the agonist-receptor complex has formed [l, 21. Effecters may be ion channels or enzymes (e.g. adenylate cyclase). In the case where they are channels, receptor-mediated permeability changes can arise in two possible ways: (a) the channel effector directly couples to the receptor, and conformational changes in the receptor molecule induced by the agonist result in conformational changes in the effector, thereby altering its permeability; or (b) activation of the receptor indirectly leads to the change in permeability by activating some intracellular metabolic pathway that causes the change. Prolonged exposure of receptors to agonist (over-stimulation) may lead to changes in the receptor, the effector, or the receptor-effector coupling. The result is desensitization which is likely a necessary consequence of activation for many neurotransmitter receptors. Different receptors can interact with common effecters and would therefore cause identical changes within the cell when these receptors are activated. In addition, the same receptor could be linked to different effecters on different cell types and, therefore, upon activation cause changes peculiar to the cell type. It is possible that some receptors for a neurotransmitter lack effecters on certain cell types, and in this case the receptors would be nonfunctioning.