Effect of genetic variation in <i>Kv1.3</i> on olfactory function

Guthoff, Martina; Tschritter, Otto; Berg, Daniela; Liepelt, Inga; Schulte, Claudia; Machicao, Fausto; Haering, Hans-Ulrich; Fritsche, Andreas

doi:10.1002/dmrr.979

Cited by 33 publications

(35 citation statements)

References 65 publications

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“…Kv1.3 knockout through gene deletion in mice led to increased insulin sensitivity and improved glucose metabolism [71] coupled with a 'super smeller' phenotype (lower olfactory detection threshold and higher olfactory discrimination scores) [74]. Consistent with this finding was a significant olfactory impairment in male homozygous carriers of a polymorphism of the human Kv1.3 (resulting in an additional Kv1.3 channel), leading to impairment of olfactory function [75]. Acute application of insulin to mitral cells obtained from lean mice led to increased excitability of in a Kv1.3-dependant manner through tyrosine phosphorylation [21,76]; however, in mice that were made prediabetic via diet-induced obesity, intranasal insulin delivery was observed to prevent autophosphorylation of Kv1.3 [77] and to modify the baseline firing of the mitral cells as well as prevent Kv1.3 modulation of olfactory function [78].…”

Section: Putative Mechanisms For Olfactory Dysfunction In Diabetesmentioning

confidence: 81%

Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions

et al. 2017

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The increasing global prevalence of diabetes mellitus presents a significant challenge to healthcare systems today. Although diabetic retinopathy, nephropathy and neuropathy are well-established complications of diabetes, there is a paucity of research examining the impact of dysglycaemia on the olfactory system. Olfaction is an important sense, playing a role in the safety, nutrition and quality of life of an individual, but its importance is often overlooked when compared with the other senses. As a result, olfactory dysfunction is often underdiagnosed. The present review article aims to present and discuss the available evidence on the relationship between diabetes and olfaction. It also explores the associations between olfactory dysfunction and diabetes complications that could explain the underlying pathogenesis. Finally, it summarizes the putative pathological mechanisms underlying olfactory dysfunction in diabetes that require further investigation.

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Section: Putative Mechanisms For Olfactory Dysfunction In Diabetesmentioning

confidence: 81%

Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions

et al. 2017

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“…Moreover, in support of a central target for metabolism, we have recently demonstrated that Kv1.3-/- mice are no longer resistant to DIO and display decreased metabolism following bilateral olfactory bulbectomy [13]. A recent polymorphism in the human Kv1.3 gene that functionally elicits a gain in function has been associated with impaired glucose tolerance, lower insulin sensitivity, and impaired olfactory ability in male homozygous carriers [41], [42]. Kv1.3 channel, as a reported “diabetes risk allele” in humans, may represent an important candidate gene for therapeutic intervention [43].…”

Section: Discussionmentioning

confidence: 98%

Mitral Cells of the Olfactory Bulb Perform Metabolic Sensing and Are Disrupted by Obesity at the Level of the Kv1.3 Ion Channel

2011

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Sixty-five percent of Americans are over-weight. While the neuroendocrine controls of energy homeostasis are well known, how sensory systems respond to and are impacted by obesity is scantily understood. The main accepted function of the olfactory system is to provide an internal depiction of our external chemical environment, starting from the detection of chemosensory cues. We hypothesized that the system additionally functions to encode internal chemistry via the detection of chemicals that are important indicators of metabolic state. We here uncovered that the olfactory bulb (OB) subserves as an internal sensor of metabolism via insulin-induced modulation of the potassium channel Kv1.3. Using an adult slice preparation of the olfactory bulb, we found that evoked neural activity in Kv1.3-expressing mitral cells is enhanced following acute insulin application. Insulin mediated changes in mitral cell excitability are predominantly due to the modulation of Kv1.3 channels as evidenced by the lack of effect in slices from Kv1.3-null mice. Moreover, a selective Kv1.3 peptide blocker (ShK186) inhibits more than 80% of the outward current in parallel voltage-clamp studies, whereby insulin significantly decreases the peak current magnitude without altering the kinetics of inactivation or deactivation. Mice that were chronically administered insulin using intranasal delivery approaches exhibited either an elevation in basal firing frequency or fired a single cluster of action potentials. Following chronic administration of the hormone, mitral cells were inhibited by application of acute insulin rather than excited. Mice made obese through a diet of ∼32% fat exhibited prominent changes in mitral cell action potential shape and clustering behavior, whereby the subsequent response to acute insulin stimulation was either attenuated or completely absent. Our results implicate an inappropriate neural function of olfactory sensors following exposure to chronic levels of the hormone insulin (diabetes) or increased body weight (obesity).

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“…Maintenance on a moderately high-fat diet reduces the number of olfactory sensory neurons while elevating insulin and glucose that we have directly shown to alter mitral cell biophysical properties in a slice configuration of the olfactory bulb. A variant in the promoter of the Kv1.3 gene (i.e., gain in channel function), and referred to as the diabetes risk allele, has recently been associated with impaired glucose tolerance, lower insulin sensitivity, higher fasting plasma glucose, and impaired olfactory dysfunction in males (Tschritter et al 2006; Guthoff et al 2009). It appears that natural changes in the sensitivity of the OB driven by modulation of Kv1.3 (in rats and humans) may contribute to the body’s metabolic response to fat intake or energy imbalance.…”

Section: Conclusion Of Nonconductive Roles For Kv13 Governing Enermentioning

confidence: 99%

The Olfactory Bulb: A Metabolic Sensor of Brain Insulin and Glucose Concentrations via a Voltage-Gated Potassium Channel

Tucker

Cavallin

Jean-Baptiste

et al. 2010

Results and Problems in Cell Differentiation

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The voltage-gated potassium channel, Kv1.3, contributes a large proportion of the current in mitral cell neurons of the olfactory bulb where it assists to time the firing patterns of action potentials as spike clusters that are important for odorant detection. Gene-targeted deletion of the Kv1.3 channel, produces a “super-smeller” phenotype, whereby mice are additionally resistant to diet- and genetically-induced obesity. As assessed via an electrophysiological slice preparation of the olfactory bulb, Kv1.3 is modulated via energetically important molecules – such as insulin and glucose – contributing to the body’s metabolic response to fat intake. We discuss a biophysical characterization of modulated synaptic communication in the slice following acute glucose and insulin stimulation, chronic elevation of insulin in mice that are in a conscious state, and induction of diet-induced obesity. We have discovered that Kv1.3 contributes an unusual nonconducting role – the detection of metabolic state.

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Effect of genetic variation in Kv1.3 on olfactory function

Abstract: The presence of genetic variation in Kv1.3 is associated with decreased olfactory function in healthy subjects. As olfactory function, glucose metabolism and genetic variation in Kv1.3 seem to be associated, further studies are needed to clarify the underlying mechanisms.

Cited by 33 publications

References 65 publications

Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions

Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions

Mitral Cells of the Olfactory Bulb Perform Metabolic Sensing and Are Disrupted by Obesity at the Level of the Kv1.3 Ion Channel

The Olfactory Bulb: A Metabolic Sensor of Brain Insulin and Glucose Concentrations via a Voltage-Gated Potassium Channel

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