S-Nitrosylation of Cardiac Ion Channels

Abstract

Nitric oxide exerts ubiquitous signaling via post-translational modification of cysteine residues, a reaction termed S-nitrosylation. Important substrates of S-nitrosylation that influence cardiac function include receptors, enzymes, ion channels, transcription factors, and structural proteins. Cardiac ion channels subserving excitation-contraction coupling are potentially regulated by S-nitrosylation. Specificity is achieved in part by spatial co-localization of ion channels with nitric oxide synthases (NOS), enzymatic sources of NO in biologic systems, and by coupling of NOS activity to localized calcium/second messenger concentrations. Ion channels regulate cardiac excitability and contractility in millisecond timescales raising the possibility that NO-related species modulate heart function on a beat-to beat basis. This review focuses on recent advances in understanding of NO regulation of the cardiac action potential, and of the calcium release channel ryanodine receptor, which is crucial for the generation of force. S-nitroso (SNO) signaling is disrupted in pathological states in which the redox state of the cell is dysregulated, including ischemia, heart failure, and atrial fibrillation.

Role of β-Adrenergic Receptors and Nitric Oxide Signaling in Exercise-Mediated Cardioprotection

“…S-nitrosylation of myocardial target proteins associated with ␤-adrenergic receptor signaling and/or calcium handling influences the contraction of the heart (31,54,69). In regard to pathophysiology, increasing the S-nitrosylation of proteins during myocardial I/R can attenuate a number of adverse processes (10,36,64), such as apoptosis (46) and inflammation (14), and even stimulate protective processes like angiogenesis (45).…”

How widespread is stable protein S-nitrosylation as an end-effector of protein regulation?

“…For example, the co-localisation of ion channels with NOS enables NO synthesis to parallel calcium concentrations. Ion channels regulate cardiac excitability and contractility with millisecond timescales, raising the possibility that thiol-reactive NO species modulate heart function via protein S-nitrosation on a beat-to beat basis [74]. Recently we reported that disulfide formation in myocardial protein kinase G I rapidly regulates diastolic relaxation [75], consistent with this oxidative modification also being capable of regulation with a millisecond timescale.…”

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

“…S-nitrosylation is referred to as the addition of an NO moiety to the thiol group of a cysteine residue (46). Like Sglutathionylation, no enzyme that can facilitate the formation of protein S-nitrosylation has been found yet.…”

“…However, enzymes like S-nitrosoglutathione reductase (GSNOR) have been shown to mediate the denitrosylation (72). Many ion channels (or their regulators) (46), including the RyR channel (4), voltage-gated sodium channel (97), the voltage-gated (6), the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (103,104), the TRP channel (140), and the K ATP channel (21,58,64,67,120), are found to be regulated by S-nitrosylation or NO.…”