Of antisense, antibodies, K+ channels, and jejunal metabolism

This month's installment of Generally Physiological focuses on endogenous regulation of K + channels by anti-sense, K + channel targeting by anti-bodies, and the effects of gastric by pass surgery on metabolism. A decrease in the abundance of voltage dependent K + channels in dorsal root ganglion (DRG) neurons can result in enhanced excitability and aberrant firing, contributing to neu-ropathic pain after peripheral nerve injury (see Han and Jan, 2013). But why should nerve injury decrease K + channel expression? Noting that long noncoding RNAs have been implicated in the regulation of gene expression, Zhao et al. (2013) determined that the DRG of various Of antisense, antibodies, K + channels, and jejunal metabolism Increased Kcna2 antisense RNA after nerve injury leads to a decrease in Kcna2, contributing to generation of neuropathic pain. (Reprinted by permission from Macmillan Publishers, Ltd. Photostimulation of a porphyrin-conjugated monoclonal antibody targeted to Kv4.2. Antisense, antibodies, K + channels, and the effects of gastric bypass surgery on metabolism mammals contained long noncod-ing RNA transcripts (Kcna2 anti-sense RNA) complementary to the RNA encoding the voltage-dependent potassium channel Kcna2. In situ hybridization revealed that expression of Kcna2 antisense RNA increased after nerve injury, whereas that of Kcna2 mRNA and Kcna2 decreased. Further analysis indicated that nerve injury increased abundance of the transcriptional activa-tor MZF1, which bound to a consensus sequence found in the Kcna2 anti-sense RNA gene promoter but not that of the Kcna2 gene, to stimulate Kcna2 antisense RNA expression. Overexpression of Kcna2 antisense RNA decreased expression of DRG Kcna2 mRNA and protein and increased the excitability of large-and medium-sized DRG neurons. Moreover, Kcna2 antisense RNA promoted hypersensitivity to mechanical stimuli and cold in mice (indicative of neuropathic pain), whereas a Kcna2 sense fragment that blocked nerve injury–induced increase in Kcna2 antisense RNA and the accompanying decrease in Kcna2 mRNA and protein attenuated such hypersensitivity. Thus, the authors conclude that Kcna2 antisense RNA represents an endogenous regulator of the Kcna2 channel in DRG and a potential target in the therapy of neuropathic pain. Targeting K + channels with antibodies Kcna2 is only one of the many voltage -gated K + (Kv) channels present in electrically excitable cells. Although the different Kv channel subtypes have distinct subcellular distributions and functional properties, the lack of subtype-selective inhibitors has made teasing out their specific contributions to cellular physiology— and pathophysiology—a challenge. In this issue, in an ingenious approach to this …