Mitochondrial Ultrastructure and Glucose Signaling Pathways Attributed to the Kv1.3 Ion Channel

Abstract

Gene-targeted deletion of the potassium channel Kv1.3 (Kv1.3−∕−) results in “Super-smeller” mice with a sensory phenotype that includes an increased olfactory ability linked to changes in olfactory circuitry, increased abundance of olfactory cilia, and increased expression of odorant receptors and the G-protein, Golf. Kv1.3−∕− mice also have a metabolic phenotype including lower body weight and decreased adiposity, increased total energy expenditure (TEE), increased locomotor activity, and resistance to both diet- and genetic-induced obesity. We explored two cellular aspects to elucidate the mechanism by which loss of Kv1.3 channel in the olfactory bulb (OB) may enhance glucose utilization and metabolic rate. First, using in situ hybridization we find that Kv1.3 and the insulin-dependent glucose transporter type 4 (GLUT4) are co-localized to the mitral cell layer of the OB. Disruption of Kv1.3 conduction via construction of a pore mutation (W386F Kv1.3) was sufficient to independently translocate GLUT4 to the plasma membrane in HEK 293 cells. Because olfactory sensory perception and the maintenance of action potential (AP) firing frequency by mitral cells of the OB is highly energy demanding and Kv1.3 is also expressed in mitochondria, we next explored the structure of this organelle in mitral cells. We challenged wildtype (WT) and Kv1.3−∕− male mice with a moderately high-fat diet (MHF, 31.8 % kcal fat) for 4 months and then examined OB ultrastructure using transmission electron microscopy. In WT mice, mitochondria were significantly enlarged following diet-induced obesity (DIO) and there were fewer mitochondria, likely due to mitophagy. Interestingly, mitochondria were significantly smaller in Kv1.3−∕− mice compared with that of WT mice. Similar to their metabolic resistance to DIO, the Kv1.3−∕− mice had unchanged mitochondria in terms of cross sectional area and abundance following a challenge with modified diet. We are very interested to understand how targeted disruption of the Kv1.3 channel in the OB can modify TEE. Our study demonstrates that Kv1.3 regulates mitochondrial structure and alters glucose utilization; two important metabolic changes that could drive whole system changes in metabolism initiated at the OB.

Modulation of olfactory-driven behavior by metabolic signals: role of the piriform cortex

“…Having these three proteins co-localized would facilitate their functional interaction. It is known that Kv1.3 is a substrate for insulin phosphorylation in the N-and C-termini of the channel (Fadool and Levitan 1998;Fadool et al 2000) and that block of the channel causes an upregulation of GLUT4 translocation for a transporter that is insulin dependent (Kovach et al 2016;Li et al 2006).…”

“…The molecular and cellular mechanisms underlying glucose and insulin sensing in the OB have been localized to MCs that express the insulin receptor (IR) (Aime et al 2012), glucose transporter type 4 (GLUT4) (Al , and the voltage-gated potassium channel, Kv1.3 (Fadool and Levitan 1998;Fadool et al 2000). Kv1.3 channels are substrates for insulin phosphorylation (Colley et al 2007;Fadool et al 2000;Marks et al 2009) whereas a decrease in Kv1.3 conductance can increase GLUT4 translocation to the membrane in a calcium-dependent manner to increase glucose uptake (Kovach et al 2016;Li et al 2006;Xu et al 2004). Previously we have suggested that modulation of GLUT4 expression in the OB that is related to food intake (Al could be responsible for the difference in olfactory sensitivity observed between satiated and fasted rats (Aime et al 2007).…”

Mitral cells and the glucagon‐like peptide 1 receptor: The sweet smell of success?

“…Intriguingly, another mechanism of action of GLP‐1 analogues could be through the inhibition of the potassium channel Kv1.3 through the activation of protein kinase A (PKA) (Chung & Schlichter, ; Kovach et al., ; Thiebaud et al., ). This channel is highly expressed by MCs, where it controls 60%–80% of outward potassium currents (Fadool & Levitan, ; Fadool et al., ) and it is overexpressed in microglia upon inflammation (Fordyce, Jagasia, Zhu, & Schlichter, ) and in AD patients (Rangaraju, Gearing, Jin, & Levey, ).…”

“…This channel is highly expressed by MCs, where it controls 60%–80% of outward potassium currents (Fadool & Levitan, ; Fadool et al., ) and it is overexpressed in microglia upon inflammation (Fordyce, Jagasia, Zhu, & Schlichter, ) and in AD patients (Rangaraju, Gearing, Jin, & Levey, ). The inhibition of Kv1.3 has shown beneficial effects that mitigate inflammation (Fordyce et al., ; Koeberle & Schlichter, ; Thomas et al., ), improve mitochondrial functions and resistance (Kovach et al., ) and inhibit apoptosis through the prevention of BAX‐induced cytochrome c release (Gulbins, Sassi, Grassmè, Zoratti, & Szabò, ; Szabó et al., ).…”

Elevated Anxiety and Impaired Attention in Super-Smeller, Kv1.3 Knockout Mice

“…We and others described a thin body type and resistance to diet-induced obesity in the Kv1.3−/− mice that was linked to the conductance of the channel (Xu et al, 2003 ; Fadool et al, 2004 , 2011 ). Thus, we became curious as to whether olfaction, metabolism and anxiety were interrelated (Palouzier-Paulignan et al, 2012 ; Krusemark et al, 2013 ; Kovach et al, 2016 ).…”