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Dopaminergic modulation of the voltage-gated sodium current in the cochlear afferent neurons of the rat.

Valdés-Baizabal C, Soto E, Vega R - PLoS ONE (2015)

Bottom Line: Recordings of the INa showed that DA receptor activation induced a significant inhibition of the peak current amplitude, leading to a significant decrease in cell excitability.The action of the D1- and D2-like receptors was shown to be mediated by a Gαs/AC/cAMP/PKA and Gαq/PLC/PKC pathways respectively.These results showed that DA receptor activation constitutes a significant modulatory input to SGNs, effectively modulating their excitability and information flow in the auditory pathway.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Puebla, México.

ABSTRACT
The cochlear inner hair cells synapse onto type I afferent terminal dendrites, constituting the main afferent pathway for auditory information flow. This pathway receives central control input from the lateral olivocochlear efferent neurons that release various neurotransmitters, among which dopamine (DA) plays a salient role. DA receptors activation exert a protective role in the over activation of the afferent glutamatergic synapses, which occurs when an animal is exposed to intense sound stimuli or during hypoxic events. However, the mechanism of action of DA at the cellular level is still not completely understood. In this work, we studied the actions of DA and its receptor agonists and antagonists on the voltage-gated sodium current (INa) in isolated cochlear afferent neurons of the rat to define the mechanisms of dopaminergic control of the afferent input in the cochlear pathway. Experiments were performed using the voltage and current clamp techniques in the whole-cell configuration in primary cultures of cochlear spiral ganglion neurons (SGNs). Recordings of the INa showed that DA receptor activation induced a significant inhibition of the peak current amplitude, leading to a significant decrease in cell excitability. Inhibition of the INa was produced by a phosphorylation of the sodium channels as shown by the use of phosphatase inhibitor that produced an inhibition analogous to that caused by DA receptor activation. Use of specific agonists and antagonists showed that inhibitory action of DA was mediated both by activation of D1- and D2-like DA receptors. The action of the D1- and D2-like receptors was shown to be mediated by a Gαs/AC/cAMP/PKA and Gαq/PLC/PKC pathways respectively. These results showed that DA receptor activation constitutes a significant modulatory input to SGNs, effectively modulating their excitability and information flow in the auditory pathway.

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Effects of D1 related drugs on the INa.A) Recordings of the INa in control condition and after perfusion of A-68930 (300 nM). B) Current-voltage relationship of the INa under control conditions and after 300 nM A-68930. The maximum decrease of the current was 29 ± 4% at −10 mV. C) Steady state inactivation of the INa in control conditions and after 300 nM A-68930, which caused a leftward shift of the inactivation. D). Bar graph comparing the inhibitory effect of 100 nM dihidrexidine with A-68930 effect. Non-significant difference was found (P = 0.445; unpaired t-test). E) Current-voltage relationship of the INa in control conditions (with 100 μM SCH-23390), and after the co-application of 300 nM A-68930. F) Steady state inactivation of the INa in control (with 100 μM SCH-23390) and after A-68930 + SCH-23390, which caused non-significant changes. G) Typical recordings of the INa showing that SCH-23390 significantly reduced the inhibitory action of 300 nM A-68930.
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pone.0120808.g004: Effects of D1 related drugs on the INa.A) Recordings of the INa in control condition and after perfusion of A-68930 (300 nM). B) Current-voltage relationship of the INa under control conditions and after 300 nM A-68930. The maximum decrease of the current was 29 ± 4% at −10 mV. C) Steady state inactivation of the INa in control conditions and after 300 nM A-68930, which caused a leftward shift of the inactivation. D). Bar graph comparing the inhibitory effect of 100 nM dihidrexidine with A-68930 effect. Non-significant difference was found (P = 0.445; unpaired t-test). E) Current-voltage relationship of the INa in control conditions (with 100 μM SCH-23390), and after the co-application of 300 nM A-68930. F) Steady state inactivation of the INa in control (with 100 μM SCH-23390) and after A-68930 + SCH-23390, which caused non-significant changes. G) Typical recordings of the INa showing that SCH-23390 significantly reduced the inhibitory action of 300 nM A-68930.

Mentions: Two D1-like agonists were studied A-68930 and dihydrexidine. The perfusion of the D1-like agonist 300 nM A-68930 (n = 14) decreased the INa amplitude 29 ± 4% (P < 0.001) (Fig. 4A-B) and shifted the V½ of the inactivation curve 7 mV leftward (P < 0.001), with no change in the slope of inactivation (Fig. 4C). Experiments using the D1 agonist dihydrexidine (100 nM) shown that it also inhibits INa 23 ± 6% (P = 0.009, n = 5; Fig. 4D) and displaced the inactivation V½ 10 mV to more negative potentials (from −71 mV in control to-81 mV; P = 0.01).


Dopaminergic modulation of the voltage-gated sodium current in the cochlear afferent neurons of the rat.

Valdés-Baizabal C, Soto E, Vega R - PLoS ONE (2015)

Effects of D1 related drugs on the INa.A) Recordings of the INa in control condition and after perfusion of A-68930 (300 nM). B) Current-voltage relationship of the INa under control conditions and after 300 nM A-68930. The maximum decrease of the current was 29 ± 4% at −10 mV. C) Steady state inactivation of the INa in control conditions and after 300 nM A-68930, which caused a leftward shift of the inactivation. D). Bar graph comparing the inhibitory effect of 100 nM dihidrexidine with A-68930 effect. Non-significant difference was found (P = 0.445; unpaired t-test). E) Current-voltage relationship of the INa in control conditions (with 100 μM SCH-23390), and after the co-application of 300 nM A-68930. F) Steady state inactivation of the INa in control (with 100 μM SCH-23390) and after A-68930 + SCH-23390, which caused non-significant changes. G) Typical recordings of the INa showing that SCH-23390 significantly reduced the inhibitory action of 300 nM A-68930.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359166&req=5

pone.0120808.g004: Effects of D1 related drugs on the INa.A) Recordings of the INa in control condition and after perfusion of A-68930 (300 nM). B) Current-voltage relationship of the INa under control conditions and after 300 nM A-68930. The maximum decrease of the current was 29 ± 4% at −10 mV. C) Steady state inactivation of the INa in control conditions and after 300 nM A-68930, which caused a leftward shift of the inactivation. D). Bar graph comparing the inhibitory effect of 100 nM dihidrexidine with A-68930 effect. Non-significant difference was found (P = 0.445; unpaired t-test). E) Current-voltage relationship of the INa in control conditions (with 100 μM SCH-23390), and after the co-application of 300 nM A-68930. F) Steady state inactivation of the INa in control (with 100 μM SCH-23390) and after A-68930 + SCH-23390, which caused non-significant changes. G) Typical recordings of the INa showing that SCH-23390 significantly reduced the inhibitory action of 300 nM A-68930.
Mentions: Two D1-like agonists were studied A-68930 and dihydrexidine. The perfusion of the D1-like agonist 300 nM A-68930 (n = 14) decreased the INa amplitude 29 ± 4% (P < 0.001) (Fig. 4A-B) and shifted the V½ of the inactivation curve 7 mV leftward (P < 0.001), with no change in the slope of inactivation (Fig. 4C). Experiments using the D1 agonist dihydrexidine (100 nM) shown that it also inhibits INa 23 ± 6% (P = 0.009, n = 5; Fig. 4D) and displaced the inactivation V½ 10 mV to more negative potentials (from −71 mV in control to-81 mV; P = 0.01).

Bottom Line: Recordings of the INa showed that DA receptor activation induced a significant inhibition of the peak current amplitude, leading to a significant decrease in cell excitability.The action of the D1- and D2-like receptors was shown to be mediated by a Gαs/AC/cAMP/PKA and Gαq/PLC/PKC pathways respectively.These results showed that DA receptor activation constitutes a significant modulatory input to SGNs, effectively modulating their excitability and information flow in the auditory pathway.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Puebla, México.

ABSTRACT
The cochlear inner hair cells synapse onto type I afferent terminal dendrites, constituting the main afferent pathway for auditory information flow. This pathway receives central control input from the lateral olivocochlear efferent neurons that release various neurotransmitters, among which dopamine (DA) plays a salient role. DA receptors activation exert a protective role in the over activation of the afferent glutamatergic synapses, which occurs when an animal is exposed to intense sound stimuli or during hypoxic events. However, the mechanism of action of DA at the cellular level is still not completely understood. In this work, we studied the actions of DA and its receptor agonists and antagonists on the voltage-gated sodium current (INa) in isolated cochlear afferent neurons of the rat to define the mechanisms of dopaminergic control of the afferent input in the cochlear pathway. Experiments were performed using the voltage and current clamp techniques in the whole-cell configuration in primary cultures of cochlear spiral ganglion neurons (SGNs). Recordings of the INa showed that DA receptor activation induced a significant inhibition of the peak current amplitude, leading to a significant decrease in cell excitability. Inhibition of the INa was produced by a phosphorylation of the sodium channels as shown by the use of phosphatase inhibitor that produced an inhibition analogous to that caused by DA receptor activation. Use of specific agonists and antagonists showed that inhibitory action of DA was mediated both by activation of D1- and D2-like DA receptors. The action of the D1- and D2-like receptors was shown to be mediated by a Gαs/AC/cAMP/PKA and Gαq/PLC/PKC pathways respectively. These results showed that DA receptor activation constitutes a significant modulatory input to SGNs, effectively modulating their excitability and information flow in the auditory pathway.

Show MeSH
Related in: MedlinePlus