Reduction in voltage‐gated K⁺ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain‐derived neurotrophic factor

Abstract

Abnormal hyperexcitability of primary sensory neurons plays an important role in neuropathic pain. Voltage-gated potassium (Kv) channels regulate neuronal excitability by affecting the resting membrane potential and influencing the repolarization and frequency of the action potential. In this study, we determined changes in Kv channels in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathic pain. The densities of total Kv, A-type (IA) and sustained delayed (IK) currents were markedly reduced in medium-and large-, but not in small-, diameter DRG neurons in diabetic rats. Quantitative RT-PCR analysis revealed that the mRNA levels of IA subunits, including Kv1.4, Kv3.4, Kv4.2, and Kv4.3, in the DRG were reduced 50% in diabetic rats compared with those in control rats. However, there were no significant differences in the mRNA levels of IK subunits (Kv1.1, Kv1.2, Kv2.1, and Kv2.2) in the DRG between the two groups.Incubation with brain-derived neurotrophic factor (BDNF) caused a large reduction in Kv currents, especially IA currents, in medium and large DRG neurons from control rats. Furthermore, the reductions in Kv currents and mRNA levels of IA subunits in diabetic rats were normalized by pre-treatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. In addition, the number of medium and large DRG neurons with BDNF immunoreactivity was greater in diabetic than control rats. Collectively, our findings suggest that diabetes primarily reduces Kv channel activity in medium and large DRG neurons. Increased BDNF activity in these neurons likely contributes to the reduction in Kv channel function through TrkB receptor stimulation in painful diabetic neuropathy.

Chronic compression of mouse dorsal root ganglion alters voltage-gated sodium and potassium currents in medium-sized dorsal root ganglion neurons

“…However, alterations in channel expression are not uniform across neuronal populations in response to different types of injury, inflammation, and other pathologies. For example, the densities of total voltage-gated K ϩ current, A-type K a current, and K dr delayed currents were markedly reduced in mediumand large-but not in small-diameter DRG neurons in painful neuropathic diabetic rats associated with the activation of brain-derived neurotrophic factor (Cao et al 2010). The in vivo application of an inflammatory agent, zymosan, to the DRG resulted in an increase in both K dr and K a currents in dissociated, small-sized neurons (Wang et al 2007).…”

Kv3.4 channel function and dysfunction in nociceptors

“…5 Others also found Kv3.4 immunoreactivity and mRNA expression in these neurons. [9][10][11]21 We isolated the rat A-type Kv3.4 current and determined its molecular identity.…”

“…[1][2][3][4][5][6] In dorsal root ganglion (DRG) nociceptors, we showed that Kv3.4 currents can be easily isolated and that Kv3.4 channels are dysregulated following spinal cord injury (SCI). 7,8 Previous to this work, Kv3.4 was detected in DRG neurons via immunohistochemistry, western blot and RT-PCR, [9][10][11] but there was no compelling isolation of the corresponding K C current. In the whole-cell configuration, a subtraction protocol revealed a Kv3.4-like current in small-diameter nociceptors.…”

Etiology and Pharmacology of Neuropathic Pain

“…Changes in K + channel currents may also contribute to pain associated with diabetic neuropathy (Cao et al, 2010).…”