Journal Article

All muscarinic acetylcholine receptors (M1-M5) are expressed in murine brain microvascular endothelium

Tsenov, Grygoriy, Osculati, Antonio Marco Maria, Radu, Beatrice Mihaela, Fabene, Paolo Francesco, Tognoli, Cristina, Kacer, Petr, Merigo, Flavia, Banciu, Adela, Di Chio, Marzia, Giorgetti, Alejandro, Suku, Eda, Radu, Mihai, Bertini, Giuseppe, Banciu, Daniel Dumitru

2017

Overview

Clinical and experimental studies indicate that muscarinic acetylcholine receptors are potential pharmacological targets for the treatment of neurological diseases. Although these receptors have been described in human, bovine and rat cerebral microvascular tissue, a subtype functional characterization in mouse brain endothelium is lacking. Here, we show that all muscarinic acetylcholine receptors (M 1 -M 5 ) are expressed in mouse brain microvascular endothelial cells. The mRNA expression of M 2 , M 3 , and M 5 correlates with their respective protein abundance, but a mismatch exists for M 1 and M 4 mRNA versus protein levels. Acetylcholine activates calcium transients in brain endothelium via muscarinic, but not nicotinic, receptors. Moreover, although M 1 and M 3 are the most abundant receptors, only a small fraction of M 1 is present in the plasma membrane and functions in ACh-induced Ca 2+ signaling. Bioinformatic analyses performed on eukaryotic muscarinic receptors demonstrate a high degree of conservation of the orthosteric binding site and a great variability of the allosteric site. In line with previous studies, this result indicates muscarinic acetylcholine receptors as potential pharmacological targets in future translational studies. We argue that research on drug development should especially focus on the allosteric binding sites of the M 1 and M 3 receptors.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/58 / 119/118 / 14/1 / 14/19 / 14/34 / 631/114/2397 / 631/443/1338 / 631/45/612/194 / 631/80/86/1999 / Acetylcholine - pharmacology / Acetylcholine receptors (muscarinic) / Allosteric properties / Allosteric Site / Animals / Binding Sites / Brain - blood supply / Calcium Signaling - drug effects / Calcium signalling / Drug development / Endothelial cells / Endothelial Cells - drug effects / Endothelial Cells - metabolism / Endothelium / Endothelium, Vascular - cytology / Endothelium, Vascular - metabolism / Gene expression / Humanities and Social Sciences / Mice, Inbred BALB C / Microvasculature / Microvessels - metabolism / multidisciplinary / Neurological diseases / Receptors, Muscarinic - chemistry / Receptors, Muscarinic - metabolism / Receptors, Nicotinic - metabolism / Rodents / Science / Science (multidisciplinary)