One gene - two proteins: The C-terminus of the prototypical M2 muscarinic receptor localizes to the mitochondria

Abstract

AbstractMuscarinic acetylcholine receptors are prototypical G protein-coupled receptors activated by the endogenous neurotransmitter acetylcholine. We show here that the carboxyl terminal fragment of the muscarinic M2receptor, containing the transmembrane regions VI and VII (M2tail), is expressed by virtue of an internal ribosome entry site. The M2tail fragment, whose expression is upregulated in cells undergoing integrated stress response, does not follow the normal route to the plasma membrane, but is almost exclusively sorted to mitochondria: here it controls oxygen consumption, cell proliferation and the formation of reactive oxygen species via reduction of oxidative phosphorylation. The expression of the carboxyl-terminal of a G protein-coupled receptor, capable of regulating mitochondrial function, constitutes a hitherto unknown mechanism that cells may use for controlling their metabolism under variable environmental conditions.