Choline is a necessary substrate of the lipid membrane and for acetylcholine synthesis. Accumulating evidence indicates that besides being a structural component, choline is also a functional modulator of the membrane. It has been shown to be a muscarinic acetylcholine receptor (mAChR) agonist and can induce a novel K+ current in cardiac cells. However, the potential role of choline in modulating cardiac functions remained unstudied despite that mAChRs are known to be important in regulating heart functions. With microelectrode techniques, we found that choline produced concentration-dependent (0.1 approximately 10 mm) decreases in sinus rhythm and action potential duration in isolated guinea pig atria. The effects were reversed by 2 nm 4DAMP (an M3-selective antagonist). Whole-cell patch-clamp recordings in dispersed myocytes from guinea pig and canine atria revealed that choline is able to induce a K+ current with delayed rectifying properties. The choline-induced current was suppressed by low concentrations of 4DAMP (2 approximately 10 nm). Antagonists toward other subtypes (M1, M2 or M4) all failed to alter the current. The affinity of choline (Kd) at mAChRs derived from displacement binding of [3H]-NMS in the homogenates from dog atria was 0.9 mm, consistent with the concentration needed for the current induction and for the HR and APD modulation. Our data indicate that choline modulates the cellular electrical properties of the hearts, likely by activating a K+ current via stimulation of M3 receptors.

Muscarinic 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 M2 receptor, 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.