The erg‐like potassium current in rat lactotrophs

Abstract

In rat lactotrophs from primary culture an inward-rectifying K¤ current is present which is characterized by sustained inward currents at membrane potentials more positive than −50 mV and by transient K¤ currents at more negative membrane potentials, when measured in high KCl external solution (Corrette et al. 1996). This current is similar to the inward-rectifying K¤ current (IK,IR) in clonal rat pituitary cells (GH×ÏBÜ cells;Bauer et al. 1990). However, in contrast to GH×ÏBÜ cells, the time course of current decay of the inwardrectifying K¤ current in most native lactotrophs exhibited a considerable slowly deactivating current component at negative membrane potentials. Characteristically, the contribution of this slow inward current component varied from cell to cell. A quantitative analysis of this new property of the inward-rectifying K¤ current was not possible because it could not be isolated from the other K¤ currents present in these cells (Corrette et al. 1996).The characteristic gating properties of IK,IR in GH×ÏB6 cells and its selective block by E_4031 and other class III antiarrhythmics (Weinsberg et al. 1997) indicated that it is mediated by K¤ channels expressed by the rat homologue of the human ether-à-go-go-related gene (erg; Sanguinetti et al. 1995;Trudeau et al. 1995). Further experiments provided evidence that the erg-mediated current is indeed a direct correlate of IK,IR in GH×ÏBÜ cells . The pharmacological isolation of the inward-rectifying K¤ current as the E_4031-sensitive current allowed measurement of this current in 5 mÒ external K¤ and demonstrated that in GH×ÏBÜ cells it provides an outward current with a maximum amplitude near −40 mV. This outward current was inhibited by thyrotrophin-releasing hormone (TRH) and this effect is involved in the TRH-induced depolarization characterizing the second phase of the TRH response in GH×ÏBÜ cells (Bauer, 1998 1. The ether-à-go-go-related gene (erg)-like K¤ current in rat lactotrophs from primary culture was characterized and compared with that in clonal rat pituitary cells (GH×ÏBÜ). The class III antiarrhythmic E_4031 known to block specifically erg K¤ channels was used to isolate the erg-like current as the E_4031-sensitive current. The experiments were performed in 150 mÒ K¤ external solution using the patch-clamp technique. 2. The erg-like K¤ current elicited with hyperpolarizing pulses negative to −100 mV consisted of a fast and a pronounced slowly deactivating current component. The contribution of the slow component to the total current amplitude was potential dependent and varied from cell to cell. At −100 mV it ranged from 50 to 85 % and at −140 mV from 21 to 45%. 3. The potential-dependent channel availability curves determined with 2 s prepulses were fitted with the sum of two Boltzmann functions. The function related to the slowly deactivating component of the erg-like current was shifted by more than 40 mV to more negative membrane potentials compared with that of the fast component. 4. In contrast to that of native lactotrophs st...

Characterization of Inhibition by Risperidone of the Inwardly Rectifying K+ Current in Pituitary GH3 Cells

“…One component is an inwardly-rectifying K ϩ current (I K(IR) ) which exhibits the voltage-dependent activation and current decay during the hyperpolarizing pulses, whereas the other component is a sustained inward current which can be activated at potentials equal or positive to Ϫ50 mV. Consistent with a previous report (Schäfer et al 1999), this study demonstrates that like E-4031, risperidone is capable of blocking I K(IR) with an IC 50 value of 1 M, whereas the sustained inward component was not affected by risperidone.…”

“…Pituitary GH 3 lactotrophs, in addition to the presence of voltage-dependent K ϩ and Ca 2 ϩ currents, have been found to exhibit the inwardly rectifying K ϩ current (I K(IR) ) (Bauer et al 1990;Wu et al 1998) which, on the basis of biophysical and pharmacological properties, was identified as an erg -mediated K ϩ current (Schäfer et al 1999;Schwarz and Bauer 1999). This current was sensitive to caffeine, thyrotropin-releasing hormone, and class III antiarrhythmic agents (e.g., E-4031), and proposed to be an important determinant of the resting membrane potential (Bauer et al 1990;Barros et al 1994Barros et al , 1996Barros et al , 1997Weinsberg et al 1997;Bauer 1998;Schwarz and Bauer 1999).…”

“…A recent report also showed that risperidone effectively blocked the inwardly rectifying erg current in native rat lactotrophs (Schäfer et al 1999). To date, however, there is little, if any, evidence to suggest that there is the underlying mechanism of actions of the neuroleptic drugs (e.g., risperidone) on ionic currents in pituitary lactotrophs.…”

Cloning and Functional Characterization of the Smooth Muscle Ether-a-go-go-related Gene K+ Channel

“…These features of HERG channel dictate its role in repolarization of the cardiac action potential and frequency-dependent modulation of the action potential duration (11). Recent studies also suggest that an inwardly rectifying K ϩ conductance that is active near the resting membrane potential of gastrointestinal smooth muscle cells (12,13), pituitary cells (14 -16), carotid body (15)(16)(17), and microglia (18) has properties similar to that of HERG channels. In these cells HERG conductance has been directly demonstrated in single cells, and in esophageal and stomach smooth muscle the presence of a "window" current within the range of the resting potential and depolarization and contraction by HERG channel blockers of whole tissue segments strongly suggest a role for ether-a-gogo-related gene K ϩ conductance in maintaining resting membrane potential (12).…”

Multiple Interactions between Cytoplasmic Domains Regulate Slow Deactivation of Kv11.1 Channels

“…Members of the KCNH family share relatively close sequence homology but differ in the voltage dependence and kinetics of channel gating. The resulting diversity in current phenotype allows KCNH family members to perform a diverse range of physiological roles in the heart, during neuronal action potential firing (2), during phasic contraction in a range of smooth muscles (3,4), in hormone secretion (5)(6)(7), and in cell proliferation (8).…”