Modulation of Neuronal Voltage-Activated Calcium and Sodium Channels by Polyamines and pH

Chen, Wenyan; Harnett, Mark T.; Smith, Stephen M.

doi:10.4161/chan.4988

Cited by 14 publications

(21 citation statements)

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“…Similar insensitivity of Na V current to 5 mM extracellular spermidine was observed in experiments using dissociated rat superior cervical ganglion neurons; however, high concentrations of external PAs appear to reduce sensitivity to block by tetrodotoxin in these neurons. 36 A prolonged 30 min exposure of transfected HEK293 cells to 1 mM extracellular spermidine or spermine suppresses the time course of recovery from inward rectification in the whole-cell mode (Fig. 5), suggesting that slow cellular uptake of PAs by endocytosis or transport proteins 5,6 may be a physiological mechanism of Na V channel modulation.…”

Section: Discussionmentioning

confidence: 96%

“…3,[19][20][21] Known interactions of PAs with ion channels include: intracellular block of K IR channels; [22][23][24] permeant block of AMPA, kainate, and NMDA subtypes of glutamate receptor channels (GluR) from both sides of the membrane; 3,[25][26][27][28] potentiation of NMDA GluR channels from the external side; 3,27 intracellular block of neuronal nicotinic acetylcholine receptor channels; 29 permeant block of olfactory and visual cyclic nucleotide-gated channels from both sides; 30,31 permeant block of the human lymphocyte TRPM7 channel from the external side; 32 activation of excitatory currents through the TRPV1 capsaicin receptor channel of sensory afferent nociceptive neurons from the external side; 33 inhibition of L-type voltagegated Ca 2+ channels (Ca V ) of smooth muscle from both sides of the membrane; 34,35 external block and positive voltage shift of activation gating of N-type Ca V channels of superior cervical ganglion neurons. 36 Studies of ion permeation through the voltage-gated Na + channel (Na V ) of rat skeletal muscle revealed that certain mutations of selectivity filter residues (i.e., K1237A) enhance the permeation of large organic cation molecules that normally block the channel. [36][37][38] This line of research led to the observation that outward Na + currents through the cloned rat muscle Na V channel expressed in human fibroblast HEK293 cells exhibit a slow time-dependent increase in the whole-cell recording mode, as if an endogenous intracellular blocking substance is slowly diluted by exchange with the pipette solution.…”

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confidence: 99%

“…36 Studies of ion permeation through the voltage-gated Na + channel (Na V ) of rat skeletal muscle revealed that certain mutations of selectivity filter residues (i.e., K1237A) enhance the permeation of large organic cation molecules that normally block the channel. [36][37][38] This line of research led to the observation that outward Na + currents through the cloned rat muscle Na V channel expressed in human fibroblast HEK293 cells exhibit a slow time-dependent increase in the whole-cell recording mode, as if an endogenous intracellular blocking substance is slowly diluted by exchange with the pipette solution. 39 When applied to the intracellular side of excised macropatches containing the skeletal muscle isoform of Na V channels, spermidine and spermine mimicked this behavior by producing strong voltage-dependent block of outward current at concentrations in the range of 1-100 mM.…”

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confidence: 99%

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Sensitivity of cloned muscle, heart and neuronal voltage-gated sodium channels to block by polyamines

Cummins

Moczydlowski

2012

Channels

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Spermidine and spermine, are endogenous polyamines (PAs) that regulate cell growth and modulate the activity of numerous ion channel proteins. In particular, intracellular PAs are potent blockers of many different cation channels and are responsible for strong suppression of outward K + current, a phenomenon known as inward rectification characteristic of a major class of K IR K + channels. We previously described block of heterologously expressed voltage-gated Na + channels (Na V ) of rat muscle by intracellular PAs and PAs have recently been found to modulate excitability of brain neocortical neurons by blocking neuronal Na V channels. In this study, we compared the sensitivity of four different cloned mammalian Na V isoforms to PAs to investigate whether PA block is a common feature of Na V channel pharmacology. We find that outward Na + current of muscle (Na V 1.4), heart (Na V 1.5), and neuronal (Na V 1.2, Na V 1.7) Na V isoforms is blocked by PAs, suggesting that PA metabolism may be linked to modulation of action potential firing in numerous excitable tissues. Interestingly, the cardiac Na V 1.5 channel is more sensitive to PA block than other isoforms. Our results also indicate that rapid binding of PAs to blocking sites in the Na V 1.4 channel is restricted to access from the cytoplasmic side of the channel, but plasma membrane transport pathways for PA uptake may contribute to long-term Na V channel modulation. PAs may also play a role in drug interactions since spermine attenuates the use-dependent effect of the lidocaine, a typical local anesthetic and anti-arrhythmic drug.

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Section: Discussionmentioning

confidence: 96%

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confidence: 99%

mentioning

confidence: 99%

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Sensitivity of cloned muscle, heart and neuronal voltage-gated sodium channels to block by polyamines

Cummins

Moczydlowski

2012

Channels

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“…In general, polyamines have “excitability buffer” properties as they can also negatively modulate the open probability of voltage gated Na + channels (Chen et al, 2007; Fleidervish et al, 2008). Depletion of cytosolic polyamines in layer 5 cortical pyramidal neurons results in increased amounts of openings of Na + channels producing a persistent Na + current and enhanced excitability, leading to spontaneous activity and paroxysmal discharges in these cells (Fleidervish et al, 2008).…”

Section: Modulation Of Neuronal Excitability By Cytosolic Polyaminesmentioning

confidence: 99%

Targets of polyamine dysregulation in major depression and suicide: Activity-dependent feedback, excitability, and neurotransmission

Limón

Mamdani

Hjelm

et al. 2016

Neuroscience & Biobehavioral Reviews

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Major depressive disorder (MDD) is a leading cause of disability worldwide characterized by altered neuronal activity in brain regions involved in the control of stress and emotion. Although multiple lines of evidence suggest that altered stress-coping mechanisms underlie the etiology of MDD, the homeostatic control of neuronal excitability in MDD at the molecular level is not well established. In this review, we examine past and current evidence implicating dysregulation of the polyamine system as a central factor in the homeostatic response to stress and the etiology of MDD. We discuss the cellular effects of abnormal metabolism of polyamines in the context of their role in sensing and modulation of neuronal, electrical, and synaptic activity. Finally, we discuss evidence supporting an allostatic model of depression based on a chronic elevation in polyamine levels resulting in self-sustained stress response mechanisms maintained by maladaptive homeostatic mechanisms.

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“…It is known that nicotine produced the elevation of [Ca 2+ ]i via nicotinic receptors (ion channel type) and L-type Ca 2+ channels in Beta-TC6 cells (Ohtani et al, 2006). It has been demonstrated that polyamines modulate various ion channels including voltage-dependent Ca 2+ channels in neurons (Chen et al, 2007). However, it appears that spermidine is not associated with the regulation of the ion channel function in Beta-TC6 insulinoma cells.…”

Section: Discussionmentioning

confidence: 95%

Spermidine Regulates Insulin Synthesis and Cytoplasmic Ca2+ in Mouse Beta-TC6 Insulinoma Cells

Ohtani

Mizuno

Kojima

et al. 2009

Cell Struct. Funct.

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ABSTRACT. In order to assess the functional role of the polyamines spermidine and spermine in pancreatic betacells, we examined the effect of spermidine and spermine synthase inhibitors, trans-4-methylcyclohexylamine (MCHA) and N-(3-aminopropyl)cyclohexylamine (APCHA), on cellular polyamine and insulin contents, insulin secretion, and cytoplasmic Ca 2+ concentration ([Ca 2+ ]i) in mouse insulin-secreting Beta-TC6 cells. The cellular spermidine and spermine contents were reduced 90% and 64% by cultivation of cells in the presence of MCHA and APCHA for 3 days, respectively. Addition of spermidine or spermine reversed the polyamine level reduced by MCHA or APCHA, respectively. Insulin secretion was decreased 40~60% in the cells treated with MCHA or APCHA. The reduction by MCHA was reversed to the untreated level by adding spermidine exogenously, while the effect of APCHA was not reversed by treatment with spermine. The cellular insulin content was also reduced by treatment with MCHA but not the expression of insulin 1 and 2 genes, suggesting that spermidine was involved in the translation of insulin mRNAs. The elevation of [Ca 2+ ]i, a key event triggering insulin secretion induced by glucose, was reduced in Beta-TC6 cells by MCHA treatment. The spermidine synthase inhibitor also augmented the sustained [Ca 2+ ]i rise induced by carbamylcholine but not by a high concentration of KCl or nicotine. These results suggested that spermidine rather than spermine plays an important role in the regulation of insulin synthesis and the glucose-induced [Ca 2+ ]i rise in Beta-TC6 cells.

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Modulation of Neuronal Voltage-Activated Calcium and Sodium Channels by Polyamines and pH

Cited by 14 publications

References 50 publications

Sensitivity of cloned muscle, heart and neuronal voltage-gated sodium channels to block by polyamines

Sensitivity of cloned muscle, heart and neuronal voltage-gated sodium channels to block by polyamines

Targets of polyamine dysregulation in major depression and suicide: Activity-dependent feedback, excitability, and neurotransmission

Spermidine Regulates Insulin Synthesis and Cytoplasmic Ca2+ in Mouse Beta-TC6 Insulinoma Cells

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