ABSTRACT
Kv10.1 is a voltage-dependent K channel whose ectopic expression is associated with several human cancers. Additionally, Kv10.1 has structure-function properties which are not yet well understood. We are using drugs of clinical importance in an attempt to gain insight on the relationship between pharmacology and characteristic functional properties of this channel. Herein, we report the interaction of desethylamiodarone (desAd), the active metabolic product of the antiarrhythmic amiodarone with Kv10.1: desAd binds to both closed and open channels, with most inhibition taking place from the open state, with affinity ~ 5 times smaller than that of amiodarone. Current inhibition by desAd and amiodarone is not synergistic. Upon repolarization desAd becomes trapped in Kv10.1 and thereafter dissociates slowly from closed-and-blocked channels. The addition of the Cole-Moore shift plus desAd open-pore-block time courses yields an increasing phase on the steady-state inhibition curve (H∞) at hyperpolarized holding potentials. In contrast to amiodarone, desAd does not inhibit the Kv10.1 Cole-Moore shift, suggesting that a relevant hydrophobic interaction between amiodarone and Kv10.1 participates in the inhibition of the Cole-Moore shift, which is lost with desAd.
Subject(s)
Amiodarone , Neoplasms , Humans , Ether-A-Go-Go Potassium Channels/metabolism , Amiodarone/pharmacology , Anti-Arrhythmia Agents/pharmacologyABSTRACT
Kv10.1 (Eag1, or KCNH1) is a human potassium-selective channel associated with tumor development. In this work, we study the interaction of the drug dronedarone with Kv10.1. Dronedarone presents two chemical modifications aimed to lessen side effects produced by its parent molecule, the antiarrhythmic amiodarone. Hence, our observations are discussed within the framework of a previously reported interaction of amiodarone with Kv10.1. Additionally, we show new data regarding the interaction of amiodarone with the channels. We found that, unexpectedly, the effect of dronedarone on Kv10.1 differs both quantitatively and qualitatively to that of amiodarone. Among other observations, we found that dronedarone seems to be an open-pore blocker, in contrast to the reported behavior of amiodarone, which seems to inhibit from both open and closed states. Additionally, herein we provide evidence showing that, in spite of their chemical similarity, these molecules inhibit the K+ conductance by binding to non-overlapping, independent (non-allosterically related) sites. Also, we show that, while amiodarone inhibits the Cole-Moore shift, dronedarone is unable to inhibit this voltage-dependent characteristic of Kv10.1.
Subject(s)
Dronedarone/pharmacology , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Potassium Channel Blockers/pharmacology , Action Potentials , Dronedarone/chemistry , Ether-A-Go-Go Potassium Channels/metabolism , HEK293 Cells , Humans , Structure-Activity RelationshipABSTRACT
The original publication of this article contained multiple technical errors that occurred during its production and printing. These errors included sentences and paragraphs with parts missing. The Publisher regrets these mistakes.
ABSTRACT
The ectopic overexpression of the voltage-dependent Eag1 (Kv10.1) K+ channel is associated with the cancerous phenotype in about 70% of human cancers and tumor cell lines. Recent reports showed that, compared with the canonical Shaker-related Kv family, Kv10.1 presents unique structural and functional properties. Herein, we report the interaction of the class III anti-arrhythmic compound amiodarone with Kv10.1. Using whole-cell patch clamp, we found that amiodarone inhibits Kv10.1 channel conductance with nanomolar affinity. Additionally, and interestingly, we also report that amiodarone inhibits the characteristic Cole-Moore shift of Eag1 channels. Our observations are interpreted considering the structural-functional characteristics of these channels. We conclude that amiodarone possibly binds with high affinity to the voltage sensor module, altering the gating of Kv10.1.
Subject(s)
Amiodarone/pharmacology , Ether-A-Go-Go Potassium Channels/metabolism , Potassium Channel Blockers/pharmacology , Action Potentials/drug effects , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , HEK293 Cells , Humans , Ion Channel Gating , Protein BindingSubject(s)
Antineoplastic Agents/pharmacology , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Mibefradil/pharmacology , Animals , Antihypertensive Agents/pharmacology , Biological Transport , Ether-A-Go-Go Potassium Channels/chemistry , Humans , Potassium/chemistry , Protein Binding , Protein ConformationABSTRACT
Photoreceptor cells have been identified as important structures in the organization of the circadian system responsible for the generation and expression of the electroretinogram (ERG) circadian rhythm. They are the structures where the circadian periodicity is expressed (effectors) and which transform information from external light signals to be conducted to the pacemaker in order to induce adjustments of the rhythm (synchronizers). After isolation, eyestalks perfused in a pigment dispersing hormone (PDH) solution, show significant changes in receptor potential (RP) amplitude and duration. Exogenous PDH injected into intact crayfish induces a migration of retinal shielding pigments to a light-adapted state. A single dose of PDH produces advances or delays in the circadian rhythm of response to light of visual photoreceptors. All these effects depend on the circadian phase of PDH application. Consequently, the determination of the action of exogenous PDH on photoreceptor cells proved to be very helpful in understanding some mechanisms underlying the circadian organization of crayfish.
