19 Harley St, London, W1G 9QJ, UK

Nitric oxide activates ATP-sensitive potassium channels in mammalian sensory neurons: action by direct S-nitrosylation

BACKGROUND: ATP-sensitive potassium (KATP) channels in neurons regulate excitability, neurotransmitter release and mediate protection from cell-death. Furthermore, activation of KATP channels is suppressed in DRG neurons after painful-like nerve injury. NO-dependent mechanisms modulate both KATP channels and participate in the pathophysiology and pharmacology of neuropathic pain. Therefore, we investigated NO modulation of KATP channels in control and axotomized DRG neurons. RESULTS: Cell-attached and cell-free recordings of KATP currents in large DRG neurons from control rats (sham surgery, SS) revealed activation of KATP channels by NO exogenously released by the NO donor SNAP, through decreased sensitivity to [ATP]i. This NO-induced KATP channel activation was not altered in ganglia from animals that demonstrated sustained hyperalgesia-type response to nociceptive stimulation following spinal nerve ligation. However, baseline opening of KATP channels and their activation induced by metabolic inhibition was suppressed by axotomy. Failure to block the NO-mediated amplification of KATP currents with specific inhibitors of sGC and PKG indicated that the classical sGC/cGMP/PKG signaling pathway was not involved in the activation by SNAP. NO-induced activation of KATP channels remained intact in cell-free patches, was reversed by DTT, a thiol-reducing agent, and prevented by NEM, a thiol-alkylating agent. Other findings indicated that the mechanisms by which NO activates KATP channels involve direct S-nitrosylation of cysteine residues in the SUR1 subunit. Specifically, current through recombinant wild-type SUR1/Kir6.2 channels expressed in COS7 cells was activated by NO, but channels formed only from truncated isoform Kir6.2 subunits without SUR1 subunits were insensitive to NO. Further, mutagenesis of SUR1 indicated that NO-induced KATP channel activation involves interaction of NO with residues in the NBD1 of the SUR1 subunit. CONCLUSION: NO activates KATP channels in large DRG neurons via direct S-nitrosylation of cysteine residues in the SUR1 subunit. The capacity of NO to activate KATP channels via this mechanism remains intact even after spinal nerve ligation, thus providing opportunities for selective pharmacological enhancement of KATP current even after decrease of this current by painful-like nerve injury

Keywords : analogs & derivatives,Animals,ATP-Binding Cassette Transporters,Cercopithecus aethiops,chemistry,Cos Cells,Cyclic GMP,Cyclic GMP-Dependent Protein Kinases,Cysteine,cytology,drug effects,enzymology,Ganglia,Spinal,genetics,injuries,Ion Channel Gating,KATP Channels,Ligation,Male,Mammals,metabolism,Mutation,Neurons,Nitric Oxide,Nitrosation,Pain,Patch-Clamp Techniques,pharmacology,Potassium Channels,Inwardly Rectifying,Protein Structure,Tertiary,Rats,Receptors,Drug,Recombinant Proteins,S-Nitroso-N-Acetylpenicillamine,Sensory Receptor Cells,Sulfonylurea Receptors,surgery,, Oxide,Activates,Atpsensitive,Potassium,Channels, colic pain

Date of Publication : 2009 Mar 14

Authors : Kawano T;Zoga V;Kimura M;Liang MY;Wu HE;Gemes G;McCallum JB;Kwok WM;Hogan QH;Sarantopoulos CD;

Organisation : Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. tkawano@mcw.edu

Journal of Publication : Mol Pain

Pubmed Link : https://www.ncbi.nlm.nih.gov/pubmed/19284878

The London Spine Unit : Harley Street UK. Specialists in Cutting Edge Technologies for Spinal Surgery

Make an Appointment 

Trustpilot Reviews
Doctify Reviews
Top Doctor Reviews

Nitric oxide activates ATP-sensitive potassium channels in mammalian sensory neurons action by direct S-nitrosylation | Nurse counsellor

What our patients say ...

Consultant Spine Surgeon
Consultant Spine Surgeon
Consultant Spine Surgeon

This surgical technique consists of a percutaneous approach for the treatment of small to medium size hernias of the intervertebral disc by laser energy. The main objective is to reduce the intradiscal pressure in the nucleus pulposus

Laser Disc Surgery can be performed under local anaesthetic as a day case at our centre on the prestigious Harley Street.
What is London spine unit and How it Works

The London Spine Unit was established in 2005 and has successfully treated over 5000 patients. All conditions are treated.

treatment of all spinal disorders

The London Spine Unit specialises in Minimally Invasive Treatments allowing rapid recovery and return to normal function

Trusted by patients worldwide

The London Spine Unit provides the highest quality care to all patients and has VIP services for those seeking exceptional services

If you have any emergency Doctor’s need, simply call our 24 hour emergency

Your personal case manager will ensure that you receive the best possible care.

Call Now 

+44 844 589 2020
+44 203 973 8810