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Upregulation of T-type Ca2+ channels in long-term diabetes determines increased excitability of a specific type of capsaicin-insensitive DRG neurons.

Duzhyy DE, Viatchenko-Karpinski VY, Khomula EV, Voitenko NV, Belan PV - Mol Pain (2015)

Bottom Line: This upregulation was not accompanied by significant changes in biophysical properties of T-type channels suggesting that a density of functionally active channels was increased.The upregulation of T-type channels resulted in the increased neuronal excitability of these nociceptive neurons revealed by a lower threshold for action potential initiation, prominent afterdepolarizing potentials and burst firing.Capsaicin-insensitive low-pH-sensitive type of DRG neurons shows diabetes-induced upregulation of Cav3.2 subtype of T-type channels.

View Article: PubMed Central - PubMed

Affiliation: Department of General Physiology of the CNS and State Key Laboratory of Molecular and Cellular Biology, Bogomoletz Institute of Physiology of National Academy of Science of Ukraine, 4 Bogomoletz street, 01024, Kyiv, Ukraine. dduzhyy@biph.kiev.ua.

ABSTRACT

Background: Previous studies have shown that increased excitability of capsaicin-sensitive DRG neurons and thermal hyperalgesia in rats with short-term (2-4 weeks) streptozotocin-induced diabetes is mediated by upregulation of T-type Ca(2+) current. In longer-term diabetes (after the 8th week) thermal hyperalgesia is changed to hypoalgesia that is accompanied by downregulation of T-type current in capsaicin-sensitive small-sized nociceptors. At the same time pain symptoms of diabetic neuropathy other than thermal persist in STZ-diabetic animals and patients during progression of diabetes into later stages suggesting that other types of DRG neurons may be sensitized and contribute to pain. In this study, we examined functional expression of T-type Ca(2+) channels in capsaicin-insensitive DRG neurons and excitability of these neurons in longer-term diabetic rats and in thermally hypoalgesic diabetic rats.

Results: Here we have demonstrated that in STZ-diabetes T-type current was upregulated in capsaicin-insensitive low-pH-sensitive small-sized nociceptive DRG neurons of longer-term diabetic rats and thermally hypoalgesic diabetic rats. This upregulation was not accompanied by significant changes in biophysical properties of T-type channels suggesting that a density of functionally active channels was increased. Sensitivity of T-type current to amiloride (1 mM) and low concentration of Ni(2+) (50 μM) implicates prevalence of Cav3.2 subtype of T-type channels in the capsaicin-insensitive low-pH-sensitive neurons of both naïve and diabetic rats. The upregulation of T-type channels resulted in the increased neuronal excitability of these nociceptive neurons revealed by a lower threshold for action potential initiation, prominent afterdepolarizing potentials and burst firing. Sodium current was not significantly changed in these neurons during long-term diabetes and could not contribute to the diabetes-induced increase of neuronal excitability.

Conclusions: Capsaicin-insensitive low-pH-sensitive type of DRG neurons shows diabetes-induced upregulation of Cav3.2 subtype of T-type channels. This upregulation results in the increased excitability of these neurons and may contribute to nonthermal nociception at a later-stage diabetes.

No MeSH data available.


Related in: MedlinePlus

Total voltage-gated Na+ current is not significantly changed in the caps−lpH+ neurons of diabetic rats. a A representative example of Na+ currents obtained using a voltage-dependent activation protocol. b Steady-state activation curves of Na+ current in the caps−lpH+ neurons of diabetic and control rats. c Steady-state inactivation curves of Na+ current in the caps−lpH+ neurons of diabetic and control rats. n = 7 from three rats for diabetic and control groups in B and C. Differences in peak current densities were insignificant (p > 0.05). These results clearly demonstrate a lack of Na+ current modulation under diabetic conditions
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Fig7: Total voltage-gated Na+ current is not significantly changed in the caps−lpH+ neurons of diabetic rats. a A representative example of Na+ currents obtained using a voltage-dependent activation protocol. b Steady-state activation curves of Na+ current in the caps−lpH+ neurons of diabetic and control rats. c Steady-state inactivation curves of Na+ current in the caps−lpH+ neurons of diabetic and control rats. n = 7 from three rats for diabetic and control groups in B and C. Differences in peak current densities were insignificant (p > 0.05). These results clearly demonstrate a lack of Na+ current modulation under diabetic conditions

Mentions: Diabetes-induced remodeling of sodium channels may also potentially increase the neuronal excitability [9] and account for the increased excitability of the caps−lpH+ neurons in the longer-term diabetic rats. To find out whether sodium current might contribute to the increased excitability of the caps−lpH+ neurons in longer-term STZ diabetes this current was compared in the neurons of control and diabetic rats. No significant diabetes-induced changes in sodium current density were found in a whole range of tested membrane potentials in protocols for channel activation and inactivation (Fig 7). In fact, the current density in the diabetic neurons was slightly and insignificantly lower compared to control in a range of low voltage membrane potentials (up to −40 mV), at which T-type current contributes to the neuronal excitability (Fig 7b). No significant changes in parameters of Boltzmann fitting functions, Gmax, Imax, k and V50, were found in diabetes versus control for steady-state activation and inactivation of sodium current (data not shown).Fig. 7


Upregulation of T-type Ca2+ channels in long-term diabetes determines increased excitability of a specific type of capsaicin-insensitive DRG neurons.

Duzhyy DE, Viatchenko-Karpinski VY, Khomula EV, Voitenko NV, Belan PV - Mol Pain (2015)

Total voltage-gated Na+ current is not significantly changed in the caps−lpH+ neurons of diabetic rats. a A representative example of Na+ currents obtained using a voltage-dependent activation protocol. b Steady-state activation curves of Na+ current in the caps−lpH+ neurons of diabetic and control rats. c Steady-state inactivation curves of Na+ current in the caps−lpH+ neurons of diabetic and control rats. n = 7 from three rats for diabetic and control groups in B and C. Differences in peak current densities were insignificant (p > 0.05). These results clearly demonstrate a lack of Na+ current modulation under diabetic conditions
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4490764&req=5

Fig7: Total voltage-gated Na+ current is not significantly changed in the caps−lpH+ neurons of diabetic rats. a A representative example of Na+ currents obtained using a voltage-dependent activation protocol. b Steady-state activation curves of Na+ current in the caps−lpH+ neurons of diabetic and control rats. c Steady-state inactivation curves of Na+ current in the caps−lpH+ neurons of diabetic and control rats. n = 7 from three rats for diabetic and control groups in B and C. Differences in peak current densities were insignificant (p > 0.05). These results clearly demonstrate a lack of Na+ current modulation under diabetic conditions
Mentions: Diabetes-induced remodeling of sodium channels may also potentially increase the neuronal excitability [9] and account for the increased excitability of the caps−lpH+ neurons in the longer-term diabetic rats. To find out whether sodium current might contribute to the increased excitability of the caps−lpH+ neurons in longer-term STZ diabetes this current was compared in the neurons of control and diabetic rats. No significant diabetes-induced changes in sodium current density were found in a whole range of tested membrane potentials in protocols for channel activation and inactivation (Fig 7). In fact, the current density in the diabetic neurons was slightly and insignificantly lower compared to control in a range of low voltage membrane potentials (up to −40 mV), at which T-type current contributes to the neuronal excitability (Fig 7b). No significant changes in parameters of Boltzmann fitting functions, Gmax, Imax, k and V50, were found in diabetes versus control for steady-state activation and inactivation of sodium current (data not shown).Fig. 7

Bottom Line: This upregulation was not accompanied by significant changes in biophysical properties of T-type channels suggesting that a density of functionally active channels was increased.The upregulation of T-type channels resulted in the increased neuronal excitability of these nociceptive neurons revealed by a lower threshold for action potential initiation, prominent afterdepolarizing potentials and burst firing.Capsaicin-insensitive low-pH-sensitive type of DRG neurons shows diabetes-induced upregulation of Cav3.2 subtype of T-type channels.

View Article: PubMed Central - PubMed

Affiliation: Department of General Physiology of the CNS and State Key Laboratory of Molecular and Cellular Biology, Bogomoletz Institute of Physiology of National Academy of Science of Ukraine, 4 Bogomoletz street, 01024, Kyiv, Ukraine. dduzhyy@biph.kiev.ua.

ABSTRACT

Background: Previous studies have shown that increased excitability of capsaicin-sensitive DRG neurons and thermal hyperalgesia in rats with short-term (2-4 weeks) streptozotocin-induced diabetes is mediated by upregulation of T-type Ca(2+) current. In longer-term diabetes (after the 8th week) thermal hyperalgesia is changed to hypoalgesia that is accompanied by downregulation of T-type current in capsaicin-sensitive small-sized nociceptors. At the same time pain symptoms of diabetic neuropathy other than thermal persist in STZ-diabetic animals and patients during progression of diabetes into later stages suggesting that other types of DRG neurons may be sensitized and contribute to pain. In this study, we examined functional expression of T-type Ca(2+) channels in capsaicin-insensitive DRG neurons and excitability of these neurons in longer-term diabetic rats and in thermally hypoalgesic diabetic rats.

Results: Here we have demonstrated that in STZ-diabetes T-type current was upregulated in capsaicin-insensitive low-pH-sensitive small-sized nociceptive DRG neurons of longer-term diabetic rats and thermally hypoalgesic diabetic rats. This upregulation was not accompanied by significant changes in biophysical properties of T-type channels suggesting that a density of functionally active channels was increased. Sensitivity of T-type current to amiloride (1 mM) and low concentration of Ni(2+) (50 μM) implicates prevalence of Cav3.2 subtype of T-type channels in the capsaicin-insensitive low-pH-sensitive neurons of both naïve and diabetic rats. The upregulation of T-type channels resulted in the increased neuronal excitability of these nociceptive neurons revealed by a lower threshold for action potential initiation, prominent afterdepolarizing potentials and burst firing. Sodium current was not significantly changed in these neurons during long-term diabetes and could not contribute to the diabetes-induced increase of neuronal excitability.

Conclusions: Capsaicin-insensitive low-pH-sensitive type of DRG neurons shows diabetes-induced upregulation of Cav3.2 subtype of T-type channels. This upregulation results in the increased excitability of these neurons and may contribute to nonthermal nociception at a later-stage diabetes.

No MeSH data available.


Related in: MedlinePlus