Caveolar targeting links Kv1.3 with the insulin-dependent adipocyte physiology

Abstract

The voltage-dependent potassium channel Kv1.3 participates in peripheral insulin sensitivity. Genetic ablation of Kv1.3 triggers resistance to diet-induced weight gain, thereby pointing to this protein as a pharmacological target for obesity and associated type II diabetes. However, this role is under intense debate because Kv1.3 expression in adipose tissue raises controversy. We demonstrated that Kv1.3 is expressed in white adipose tissue from humans and rodents. Moreover, other channels, such as Kv1.1, Kv1.2, Kv1.4 and especially Kv1.5, from the same Shaker family are also present. Although elevated insulin levels and adipogenesis remodel the Kv phenotype, which could lead to multiple heteromeric complexes, Kv1.3 markedly participates in the insulin-dependent regulation of glucose uptake in mature adipocytes. Adipocyte differentiation increased the expression of Kv1.3, which is targeted to caveolae by molecular interactions with caveolin 1. Using a caveolin 1-deficient 3T3-L1 adipocyte cell line, we demonstrated that the localization of Kv1.3 in caveolar raft structures is important for proper insulin signaling. Insulin-dependent phosphorylation of the channel occurs at the onset of insulin-mediated signaling. However, when Kv1.3 was spatially outside of these lipid microdomains, impaired phosphorylation was exhibited. Our data shed light on the putative role of Kv1.3 in weight gain and insulin-dependent responses contributing to knowledge about adipocyte physiology.

The Potassium Channel Odyssey: Mechanisms of Traffic and Membrane Arrangement

“…Lymphocytes concentrate Kv1.3 at the immune synapse to control Ca 2+ influx during activation [7] or at the inner mitochondrial membrane to regulate apoptosis [8]. In addition, Kv1.3 targets caveolae in adipocytes participating in the insulin-dependent signaling [9]. In myocytes, Kv11.1 is targeted to the transverse tubular network, Kv7.1 is localized to the peripheral sarcolemma and T-tubules, and, finally, Kv1.5 is concentrated at the intercalated disks and in proximity to Z-lines [10,11].…”

Mitochondrialne kanały potasowe: podsumowanie

“…The activity of the mitoKv1.3 channel has been reported in mitochondria from lymphocytes [23] and brain [55]. In addition, Kv1.3 was also reported in the plasma membrane of cells in the kidney [56], adipocytes [57] and epithelia [58].…”

Caveolae and Lipid Rafts in Endothelium: Valuable Organelles for Multiple Functions

“…Although studies performed in cav-1 knockout mice revealed metabolic abnormalities [ 133 ], the underlying molecular mechanisms that link cav-1 and the caveolar network to EC metabolism are still poorly understood [ 134 ]. In adipocytes, caveolae directly participate in insulin signaling by sequestrating insulin receptor and GLUT4 and their perturbation leads to pathologic conditions related to lipid metabolism [ 135 , 136 , 137 , 138 , 139 ]. Notably, insulin resistance, defined as the lack of ability of cells to respond to insulin and to handle circulating glucose, is frequently associated with endothelial dysfunction and cardiovascular diseases.…”