Stimulation of ␣1-adrenoreceptors (␣1-AR) acutely alters ion channel behavior via several signaling pathways [calcium and protein kinase C (PKC)]. Little is known about sustained ␣1-adrenergic/PKC signaling and channel regulation as may occur during cardiovascular disease states. Here we describe the effects of prolonged ␣1A-AR and PKC activity on human ether-a-go-go-related gene (HERG) K ϩ channels (Kv11.1) expressed in a heterologous expression system. Stimulation of ␣1A-AR with phenylephrine or direct activation of PKC with phorbol ester increased HERG channel protein abundance and K ϩ current density in a time-and dose-dependent manner. Channel augmentation reached a steady-state plateau within 24 h with a 2-to 6-fold induction. Phorbol ester and moderate ␣1A-AR stimulation enhanced HERG abundance in a PKC-dependent fashion but with stronger ␣1A-adrenergic stimulation; protein kinase A (PKA)-dependent activity also contributed. Comparable channel induction of other cardiac K ϩ channels was not seen in this system. Comparison of wild-type HERG and channels with either mutated PKC phosphorylation sites (HERG⌬PKC) or mutated PKA phosphorylation sites (HERG⌬PKA) suggested that the mechanisms of augmentation of HERG by the two kinases were partially overlapping. The PKCdependent effect was largely due to enhanced synthetic rates. Stimulation of ␣1-AR in cultured rat neonatal cardiac myocytes also enhanced the abundance of ERG channels. These findings show that ␣1A-AR stimulation is capable of influencing the balance of HERG channel synthesis and degradation via multiple signaling pathways, a process that may have relevance in cardiac diseases and treatment.
Proarrhythmic drugs induce long QT syndrome more frequently in women than men. The present study was designed to determine whether androgens regulate the function and expression of the human ether-á-go-go-related gene (HERG) encoded K+ channel, which is largely responsible for determining the QT interval. In a concentration-dependent manner (10(-9) to 10(-6) M for 24 h), 5alpha-dihydrotestosterone (5alpha-DHT) increased HERG protein abundance in HEK293 cells stably expressing HERG in the presence of coexpressed cardiac androgen receptor (AR) variant [N-terminal truncated isoform of AR (AR45)]. The elevation of HERG protein was seen in endoplasmic reticulum, Golgi, and plasma membrane without clear preferential colocalization. Coexpression of the more common form of the AR did not confer 5alpha-DHT augmentation of HERG protein. Proteasome inhibitors, N-acetyl-L-leucyl-L-leucyl-L-norleucinal and MG132 prevented the 5alpha-DHT- dependent enhancement of HERG, as did the lysosome inhibitor, bafilomycin A1. Consistently, the cycloheximide-based protein chase study showed that 5alpha-DHT prolonged HERG protein half-life. 5alpha-DHT/AR45 signaling induced phosphorylation of ERK1/2. Blockade of ERK1/2 with PD98059 and U0126 prevented the effect of androgen on HERG protein abundance. Functional studies showed that 5alpha-DHT treatment for 24 h increased HERG K+ current density in Chinese hamster ovary cells cotransfected with cDNAs of AR45 and HERG channels. Moreover, 5alpha-DHT also increased ether-á-go-go-related gene-encoded K+ channel protein abundance in isolated rabbit cardiac myocytes. In conclusion, these data provide evidence that stimulation of AR45 receptors by androgens up-regulates HERG K+ channel abundance and activity mainly through stabilizing HERG protein in an ERK1/2 dependent mechanism, and suggest a mechanism to explain the sex difference in the long QT syndrome.
In this paper, an anisotropic holographic metasurface design is proposed, fabricated, and measured, to demonstrate that it can generate multiple beams with different orbital angular momentum (OAM) modes in the radio-frequency domain. The anisotropic holographic metasurface is composed of an array of quasi-periodic square particles with a rectangular slot in the upper metallic layer covered with a dielectric ground. The classic leaky-wave theory and a microwave holography method are introduced to construct the holograms that interfere with the surface waves excited by a monopole antenna and the objective waves represented by the desired multiple beams carrying different OAM modes. Moreover, the numerical simulations and experimental results are in very good agreement, which demonstrates the excellent performance of the design and provides a method of generating multiple OAM modes simultaneously. This lays a solid foundation for a channel-multiplexing method based on OAM-mode multiplexing to expand the capacity of wireless communication systems.
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