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

Abstract

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.

Computational Optogenetics: Empirically-Derived Voltage- and Light-Sensitive Channelrhodopsin-2 Model

“…Later, it was established that Mg 2+ acts at low-affinity sites, while endogenous cytosolic polyamines act on high-affinity sites and both mediate rectification. Importantly, polyamines' role in rectification was confirmed for a variety of target channels: inward rectifier, including the cardiac isoform (Kir2.1) by Lopatin and Ficker [43], [44], ryanodine receptors and their rectification properties [45], Ca 2+ sensitive AMPA receptors [46], and recently also for rectification of cloned Na + channels, especially the cardiac isoform (Nav1.5) [47]. Future work should test the possibility for polyamine-mediated rectification in ChR2; such new experimental data can form the basis for a more mechanistic description of voltage rectification within the ChR2 model.…”

Kainate receptor pore‐forming and auxiliary subunits regulate channel block by a novel mechanism

“…; Fu et al . ). In this capacity, cytoplasmic polyamines are recognized as important determinants of neuronal signalling by regulating action potential firing rates (Fleidervish et al .…”

“…Disruption in the synthesis or catabolism of polyamines leads to a variety of disease states from cancer to neurodevelopmental disorders (Nowotarski et al 2013;Pegg, 2014), underlining their physiological importance. Given their cationic nature, polyamines interact with negatively charged domains of biomolecules (Tabor & Tabor, 1984) including the electrostatic pore regions of voltage-and ligand-gated ion channels where they bind and consequently block ion flow with micromolar affinity (Lopatin et al 1994;Bowie & Mayer, 1995;Gomez & Hellstrand, 1995;Haghighi & Cooper, 1998;Lu & Ding, 1999;Kerschbaum et al 2003;Fu et al 2012). In this capacity, cytoplasmic polyamines are recognized as important determinants of neuronal signalling by regulating action potential firing rates (Fleidervish et al 2008) as well as the strength of neurotransmission (Rozov & Burnashev, 1999;Aizenman et al 2002).…”

Stargazin and cornichon-3 relieve polyamine block of AMPA receptors by enhancing blocker permeation

“…Although Mg 2+ channel block contributes to the overall mechanism of inward rectification ( Horie et al, 1987 ; Matsuda et al, 1987 ; Vandenberg, 1987 ), the discovery of polyamine block explained the steep voltage dependence of inward rectification as well as earlier observations noting that the degree of rectification dissipated in excised patches (because of blocker washout; Matsuda et al, 1987 ; Vandenberg, 1987 ). Since then, many cation-selective ion-channel families have been shown to be blocked in a voltage-dependent manner by cytoplasmic polyamines, including AMPA-type (AMPARs) and kainate-type (KARs) ionotropic glutamate receptors (iGluRs; Bowie and Mayer, 1995 ; Kamboj et al, 1995 ; Koh et al, 1995 ), voltage-activated calcium channels ( Gomez and Hellstrand, 1995 ), nicotinic acetylcholine receptors ( Haghighi and Cooper, 1998 ), cyclic nucleotide-gated (CNG) channels ( Lu and Ding, 1999 ; Guo and Lu, 2000 ), MIC/TRPM7 channels ( Kerschbaum et al, 2003 ), and voltage-gated sodium channels ( Fu et al, 2012 ). A property that has emerged from this work is that some ion channels, particularly nonselective cation channels, are also able to flux polyamines from both the inside and outside of cells as a mechanism to relieve channel block.…”