Pharmacological Conversion of a Cardiac Inward Rectifier into an Outward Rectifier Potassium Channel

Abstract

Potassium (K 1 ) channels are crucial for determining the shape, duration, and frequency of action-potential firing in excitable cells. Broadly speaking, K 1 channels can be classified based on whether their macroscopic current outwardly or inwardly rectifies, whereby rectification refers to a change in conductance with voltage. Outwardly rectifying K 1 channels conduct greater current at depolarized membrane potentials, whereas inward rectifier channels conduct greater current at hyperpolarized membrane potentials. Under most circumstances, outward currents through inwardly rectifying K 1 channels are reduced at more depolarized potentials. However, the acetylcholinegated K 1 channel (K ACh ) conducts current that inwardly rectifies when activated by some ligands (such as acetylcholine), and yet conducts current that outwardly rectifies when activated by other ligands (for example, pilocarpine and choline). The perplexing and paradoxical behavior of K ACh channels is due to the intrinsic voltage sensitivity of the receptor that activates K ACh channels, the M 2 muscarinic receptor (M2R). Emerging evidence reveals that the affinity of M2R for distinct ligands varies in a voltage-dependent and ligand-specific manner. These intrinsic receptor properties determine whether current conducted by K ACh channels inwardly or outwardly rectifies. This review summarizes the most recent concepts regarding the intrinsic voltage sensitivity of muscarinic receptors and the consequences of this intriguing behavior on cardiac physiology and pharmacology of K ACh channels.

Dimethylethanolamine Decreases Epileptiform Activity in Acute Human Hippocampal Slices in vitro

“…Nevertheless, due to structural similarities of DMEA, ACh and choline, muscarinic ACh receptors (mAChRs) present possible targets of DMEA action. ACh and choline are both ligands of M2 and M3 mAChRs (Shi et al, 2004; Moreno-Galindo et al, 2016), which upon activation increase the open probability of G-protein coupled inwardly rectifying potassium (GIRK) channels, specifically GIRK1 and GIRK4 (Nemec et al, 1999). GIRK1 and GIRK4 are expressed in the hippocampus (Miyashita and Kubo, 1997; Murer et al, 1997; Cea-del Rio et al, 2010) and pharmacological activation of GIRK results in antiepileptic effects in vitro and in vivo (Kaufmann et al, 2013).…”

Differential voltage-dependent modulation of the ACh-gated K+ current by adenosine and acetylcholine

“…Recently, in cat atrial myocytes we have shown that M 2 R exhibits agonist-specific voltage dependence, where the intrinsic voltage sensitivity of this receptor [7][8][9] modifies its affinity for diverse agonists in a ligand-selective manner, which is eventually reflected on the activation of the coupled K ACh channels [10]. This property can be distinguished in the deactivation kinetics of the current carried by these channels, I KACh [11].…”

A Latin American Perspective on Ion Channels

“…The present special issue broadcasts a series of minireviews provided by only a subset of the outstanding scientists working in Latin America. It includes the structure, function, and/or modulation of the transient receptor potential channel vanilloid 1 (Diaz-Franulic et al, 2016), K 1 channels (Moreno-Galindo et al, 2016;Niemeyer et al, 2016) and ligand-gated ion channels (Burgos et al, 2016;Calvo and Beltrán González, 2016;Corradi and Bouzat, 2016). The participation of ion channels in pathophysiology-like cell volume regulation (Pasantes-Morales, 2016), pancreatic b-cell function (Velasco et al, 2016), autophagy (Filippi-Chiela et al, 2016), and cancer (Morrone et al, 2016;Fernandez et a., 2016) is also highlighted.…”