Abstract
The question that started with the pioneering work of Otto Loewi in the 1920s, to identify how stimulation of the vagus nerve decreased heart rate, is approaching its 100th year anniversary. In the meantime, we have learned that the neurotransmitter acetylcholine acting through muscarinic M2 receptors activates cardiac potassium (Kir3) channels via the βγ subunits of G proteins, an important effect that contributes to slowing atrial pacemaker activity. Concurrent stimulation of M1 or M3 receptors hydrolyzes PIP2, a signaling phospholipid essential to maintaining Kir3 channel activity, thus causing desensitization of channel activity and protecting the heart from overinhibition of pacemaker activity. Four mammalian members of the Kir3 subfamily, expressed in heart, brain, endocrine organs, etc., are modulated by a plethora of stimuli to regulate cellular excitability. With the recent great advances in ion channel structural biology, three-dimensional structures of Kir3 channels with PIP2 and the Gβγ subunits are now available. Mechanistic insights have emerged that explain how modulatory control of activity feeds into a core mechanism of channel-PIP2 interactions to regulate the conformation of channel gates. This complex but beautiful system continues to surprise us for almost 100 years with an apparent wisdom in its intricate design.
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