During embryonic development, the subunit composition of the IK,ACh channel switches from predominantly Kir3.1 to Kir3.4, reducing inward rectification and allowing for acetylcholine-induced membrane hyperpolarization and strong negative chronotropy.
A developmental switch in IK,ACh subunit composition from Kir3.1 to Kir3.4 is responsible for the strong negative chronotropic response to parasympathetic stimulation in adult cardiomyocytes.
Parasympathetic slowing of the heart rate is predominantly mediated by acetylcholine-dependent activation of the G protein-gated potassium (K+) channel (IK,ACh). This channel is composed of 2 inward-rectifier K+ (Kir) channel subunits, Kir3.1 and Kir3.4, that display distinct functional properties. Here we show that subunit composition of IK,ACh changes during embryonic development. At early stages, IK,ACh is primarily formed by Kir3.1, while in late embryonic and adult cells, Kir3.4 is the predominant subunit. This change in subunit composition results in reduced rectification of IK,ACh, allowing for marked K+ currents over the whole physiological voltage range. As a consequence, IK,ACh is able to generate the membrane hyperpolarization that underlies the strong negative chronotropy occurring in late- but not early-stage atrial cardiomyocytes upon application of muscarinic agonists. Both strong negative chronotropy and membrane hyperpolarization can be induced in early-stage cardiomyocytes by viral overexpression of the mildly rectifying Kir3.4 subunit. Thus, a switch in subunit composition is used to adopt IK,ACh to its functional role in adult cardiomyocytes.
Fleischmann et al. (Fri,) conducted a other in Cardiac development. Developmental stage (Late vs Early embryonic stage) vs. Early embryonic stage was evaluated on Chronotropic effect and membrane hyperpolarization upon muscarinic stimulation. During embryonic development, the subunit composition of the IK,ACh channel switches from predominantly Kir3.1 to Kir3.4, reducing inward rectification and allowing for acetylcholine-induced membrane hyperpolarization and strong negative chronotropy.