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Na+-activated K+ channels express a large delayed outward current in neurons during normal physiology.

Budelli G, Hage TA, Wei A, Rojas P, Jong YJ, O'Malley K, Salkoff L - Nat. Neurosci. (2009)

Bottom Line: We found that TTX also eliminated this delayed outward component in rat neurons as a secondary consequence.Unexpectedly, we found that the activity of a persistent inward sodium current (persistent I(Na)) is highly effective at activating this large Na(+)-dependent (TTX sensitive) delayed outward current.These findings have far reaching implications for many aspects of cellular and systems neuroscience, as well as clinical neurology and pharmacology.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Washington University School of Medicine, St. Louis, Missouri, USA.

ABSTRACT
One of the largest components of the delayed outward current that is active under physiological conditions in many mammalian neurons, such as medium spiny neurons of the striatum and tufted-mitral cells of the olfactory bulb, has gone unnoticed and is the result of a Na(+)-activated K(+) current. Previous studies of K(+) currents in mammalian neurons may have overlooked this large outward component because the sodium channel blocker tetrodotoxin (TTX) is typically used in such studies. We found that TTX also eliminated this delayed outward component in rat neurons as a secondary consequence. Unexpectedly, we found that the activity of a persistent inward sodium current (persistent I(Na)) is highly effective at activating this large Na(+)-dependent (TTX sensitive) delayed outward current. Using siRNA techniques, we identified SLO2.2 channels as being carriers of this delayed outward current. These findings have far reaching implications for many aspects of cellular and systems neuroscience, as well as clinical neurology and pharmacology.

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Transient and persistent Na+ currents in MSNsa,b Transient Na+ current. b,c persistent inward Na+ current. The persistent Na+ current was plotted as the mean current during the 150–250 ms interval after the transient inward Na+ current, as indicated in “c” (n=3). 100 mM cesium ion was used in the internal pipette solution and 40 mM TEA was used in the extracellular saline to block the potassium conductances. To isolate the TTX-sensitive components, we recorded currents before and after applying TTX; we then subtracted the residual currents after TTX from the currents recorded before TTX application. Thus, the currents shown represent both the TTX-sensitive transient and persistent components. The internal pipette solution contained 40 mM Na+ to reduce the driving force of Na+ and gain better voltage control. This also reduced the amplitudes of the currents. The approximate Na+ equilibrium potential was +23 mV. Standard errors are shown.
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Figure 4: Transient and persistent Na+ currents in MSNsa,b Transient Na+ current. b,c persistent inward Na+ current. The persistent Na+ current was plotted as the mean current during the 150–250 ms interval after the transient inward Na+ current, as indicated in “c” (n=3). 100 mM cesium ion was used in the internal pipette solution and 40 mM TEA was used in the extracellular saline to block the potassium conductances. To isolate the TTX-sensitive components, we recorded currents before and after applying TTX; we then subtracted the residual currents after TTX from the currents recorded before TTX application. Thus, the currents shown represent both the TTX-sensitive transient and persistent components. The internal pipette solution contained 40 mM Na+ to reduce the driving force of Na+ and gain better voltage control. This also reduced the amplitudes of the currents. The approximate Na+ equilibrium potential was +23 mV. Standard errors are shown.

Mentions: Experiments to measure the persistent Na+ current in MSNs (Fig. 4) show a current which is only a small fraction of the peak transient Na+ current, as had been previously reported (18). Also, as previously reported, we found the persistent Na+ current to be active over a wider voltage range than the transient Na+ current, with some current noted at negative potentials of at least .−70 mV. Note that in the experiments plotted in Figure 4d we adjusted the Na+ equilibrium potential to approximately +23 mV to improve voltage control by raising internal [Na+] (Fig. legend 4). The lower driving force on Na+ resulted in a smaller sodium current than would be seen under normal physiological conditions, and showed a reversal potential close to ENa. Experiments raising ENa by lowering internal [Na+] indicated little inactivation of the persistent INa+ at voltages exceeding +23 mV.


Na+-activated K+ channels express a large delayed outward current in neurons during normal physiology.

Budelli G, Hage TA, Wei A, Rojas P, Jong YJ, O'Malley K, Salkoff L - Nat. Neurosci. (2009)

Transient and persistent Na+ currents in MSNsa,b Transient Na+ current. b,c persistent inward Na+ current. The persistent Na+ current was plotted as the mean current during the 150–250 ms interval after the transient inward Na+ current, as indicated in “c” (n=3). 100 mM cesium ion was used in the internal pipette solution and 40 mM TEA was used in the extracellular saline to block the potassium conductances. To isolate the TTX-sensitive components, we recorded currents before and after applying TTX; we then subtracted the residual currents after TTX from the currents recorded before TTX application. Thus, the currents shown represent both the TTX-sensitive transient and persistent components. The internal pipette solution contained 40 mM Na+ to reduce the driving force of Na+ and gain better voltage control. This also reduced the amplitudes of the currents. The approximate Na+ equilibrium potential was +23 mV. Standard errors are shown.
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Related In: Results  -  Collection

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Figure 4: Transient and persistent Na+ currents in MSNsa,b Transient Na+ current. b,c persistent inward Na+ current. The persistent Na+ current was plotted as the mean current during the 150–250 ms interval after the transient inward Na+ current, as indicated in “c” (n=3). 100 mM cesium ion was used in the internal pipette solution and 40 mM TEA was used in the extracellular saline to block the potassium conductances. To isolate the TTX-sensitive components, we recorded currents before and after applying TTX; we then subtracted the residual currents after TTX from the currents recorded before TTX application. Thus, the currents shown represent both the TTX-sensitive transient and persistent components. The internal pipette solution contained 40 mM Na+ to reduce the driving force of Na+ and gain better voltage control. This also reduced the amplitudes of the currents. The approximate Na+ equilibrium potential was +23 mV. Standard errors are shown.
Mentions: Experiments to measure the persistent Na+ current in MSNs (Fig. 4) show a current which is only a small fraction of the peak transient Na+ current, as had been previously reported (18). Also, as previously reported, we found the persistent Na+ current to be active over a wider voltage range than the transient Na+ current, with some current noted at negative potentials of at least .−70 mV. Note that in the experiments plotted in Figure 4d we adjusted the Na+ equilibrium potential to approximately +23 mV to improve voltage control by raising internal [Na+] (Fig. legend 4). The lower driving force on Na+ resulted in a smaller sodium current than would be seen under normal physiological conditions, and showed a reversal potential close to ENa. Experiments raising ENa by lowering internal [Na+] indicated little inactivation of the persistent INa+ at voltages exceeding +23 mV.

Bottom Line: We found that TTX also eliminated this delayed outward component in rat neurons as a secondary consequence.Unexpectedly, we found that the activity of a persistent inward sodium current (persistent I(Na)) is highly effective at activating this large Na(+)-dependent (TTX sensitive) delayed outward current.These findings have far reaching implications for many aspects of cellular and systems neuroscience, as well as clinical neurology and pharmacology.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Washington University School of Medicine, St. Louis, Missouri, USA.

ABSTRACT
One of the largest components of the delayed outward current that is active under physiological conditions in many mammalian neurons, such as medium spiny neurons of the striatum and tufted-mitral cells of the olfactory bulb, has gone unnoticed and is the result of a Na(+)-activated K(+) current. Previous studies of K(+) currents in mammalian neurons may have overlooked this large outward component because the sodium channel blocker tetrodotoxin (TTX) is typically used in such studies. We found that TTX also eliminated this delayed outward component in rat neurons as a secondary consequence. Unexpectedly, we found that the activity of a persistent inward sodium current (persistent I(Na)) is highly effective at activating this large Na(+)-dependent (TTX sensitive) delayed outward current. Using siRNA techniques, we identified SLO2.2 channels as being carriers of this delayed outward current. These findings have far reaching implications for many aspects of cellular and systems neuroscience, as well as clinical neurology and pharmacology.

Show MeSH