Regulation of Ion Channels by Pyridine Nucleotides

Abstract

Recent research suggests that in addition to their role as soluble electron carriers, pyridine nucleotides [NAD(P)(H)] also regulate ion transport mechanisms. This mode of regulation seems to have been conserved through evolution. Several bacterial ion–transporting proteins or their auxiliary subunits possess nucleotide-binding domains. In eukaryotes, the Kv1 and Kv4 channels interact with pyridine nucleotide–binding β-subunits that belong to the aldo-keto reductase superfamily. Binding of NADP+ to Kvβ removes N-type inactivation of Kv currents, whereas NADPH stabilizes channel inactivation. Pyridine nucleotides also regulate Slo channels by interacting with their cytosolic regulator of potassium conductance domains that show high sequence homology to the bacterial TrkA family of K+ transporters. These nucleotides also have been shown to modify the activity of the plasma membrane KATP channels, the cystic fibrosis transmembrane conductance regulator, the transient receptor potential M2 channel, and the intracellular ryanodine receptor calcium release channels. In addition, pyridine nucleotides also modulate the voltage-gated sodium channel by supporting the activity of its ancillary subunit—the glycerol-3-phosphate dehydrogenase-like protein. Moreover, the NADP+ metabolite, NAADP+, regulates intracellular calcium homeostasis via the 2-pore channel, ryanodine receptor, or transient receptor potential M2 channels. Regulation of ion channels by pyridine nucleotides may be required for integrating cell ion transport to energetics and for sensing oxygen levels or metabolite availability. This mechanism also may be an important component of hypoxic pulmonary vasoconstriction, memory, and circadian rhythms, and disruption of this regulatory axis may be linked to dysregulation of calcium homeostasis and cardiac arrhythmias.

Oxygen Sensing by Arterial Chemoreceptors Depends on Mitochondrial Complex I Signaling

“…We also observed a significant increase in basal levels of NAD(P)H autofluorescence in Ndufs2-null glomus cells with respect to controls ( Figure 7I). Numerous reports have indicated that pyridine nucleotides can bind to voltage-gated K + channel subunits and modulate their function (Tipparaju et al, 2005;Tamsett et al, 2009;Kilfoil et al, 2013). Loading glomus cells with NADH (150 mM in the whole-cell recording pipette), thereby mimicking the conditions that may exist in Ndufs2-deficient mice, markedly blunted the hypoxic modulation of the currents (Figures S7I and S7J).…”

High level of oxygen treatment causes cardiotoxicity with arrhythmias and redox modulation

“…Cellular redox status is an important determinant of cardiac function. Pyridine nucleotides that are major intracellular redox modulators regulate the Kv channel activity (3, 22, 24). Given the significant structural and ion channel disturbances reported in hyperoxia treated mouse hearts, we hypothesize that hyperoxia exposure leads to cardiac ion channel disturbances and redox changes resulting in arrhythmias.…”

Absence of Intracellular Ion Channels TPC1 and TPC2 Leads to Mature-Onset Obesity in Male Mice, Due to Impaired Lipid Availability for Thermogenesis in Brown Adipose Tissue

“…Pyridine nucleotides have recently been hypothesized to be essential for sensing oxygen levels and metabolite availability (20). One of these, nicotinic acid adenine dinucleotide phosphate is the most potent intracellular Ca 2ϩ mobilizer identified to date (21)(22)(23).…”