Calcium/calmodulin-dependent kinase II mediates NO-elicited PKG activation to participate in spinal reflex potentiation in anesthetized rats

Gin Den Chen, Mei Lin Peng, Pei Yi Wang, Shin Da Lee, Hung Ming Chang, Shwu Fen Pan, Mei Jung Chen, Kwong Chung Tung, Cheng Yuan Lai, Tzer Bin Lin

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Calcium/calmodulin protein kinase (CaMK)-dependent nitric oxide (NO) and the downstream intracellular messenger cGMP, which is activated by soluble guanylate cyclase (sGC), are believed to induce long-term changes in efficacy of synapses through the activation of protein kinase G (PKG). The aim of this study was to examine the involvement of the CaMKII-dependent NO/sGC/PKG pathway in a novel form of repetitive stimulation-induced spinal reflex potentiation (SRP). A single-pulse test stimulation (TS; 1/30 Hz) on the afferent nerve evoked a single action potential, while repetitive stimulation (RS; 1 Hz) induced a long-lasting SRP that was abolished by a selective Ca 2+/CaMKII inhibitor, autocamtide 2-related inhibitory peptide (AIP). Such an inhibitory effect was reversed by a relative excess of nitric oxide synthase (NOS) substrate, L-arginine. In addition, the RS-induced SRP was abolished by pretreatment with the NOS inhibitor, NG-nitro-L- arginine-methyl ester (L-NAME). The sGC activator, protoporphyrin IX (PPIX), reversed the blocking effect caused by L-NAME. On the other hand, a sGC blocker, 1H-[1, 2, 4]oxadiazolo[4, 3-α]quinoxalin-1-one (ODQ), abolished the RS-induced SRP. Intrathecal applications of the membrane-permeable cGMP analog, 8-bromoguanosine 3′,5′-cyclic monophosphate sodium salt monohydrate (8-Br-cGMP), reversed the blocking effect on the RS-induced SRP elicited by the ODQ. Our findings suggest that a CaMKII-dependent NO/sGC/PKG pathway is involved in the RS-induced SRP, which has pathological relevance to hyperalgesia and allodynia.

Original languageEnglish
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume294
Issue number2
DOIs
Publication statusPublished - Feb 2008
Externally publishedYes

Fingerprint

Cyclic GMP-Dependent Protein Kinases
Calcium-Calmodulin-Dependent Protein Kinases
Reflex
Nitric Oxide
Calcium
Calcium-Calmodulin-Dependent Protein Kinase Type 2
NG-Nitroarginine Methyl Ester
Hyperalgesia
Nitric Oxide Synthase
Quinoxalines
Synapses
Action Potentials
Arginine
Salts
Sodium
Soluble Guanylyl Cyclase
Peptides
Membranes

Keywords

  • Cyclic monophosphate sodium salt monohydrate
  • Soluble guanylate cyclase
  • Spinal cord
  • Spinal reflex potentiation
  • Windup

ASJC Scopus subject areas

  • Physiology

Cite this

Calcium/calmodulin-dependent kinase II mediates NO-elicited PKG activation to participate in spinal reflex potentiation in anesthetized rats. / Chen, Gin Den; Peng, Mei Lin; Wang, Pei Yi; Lee, Shin Da; Chang, Hung Ming; Pan, Shwu Fen; Chen, Mei Jung; Tung, Kwong Chung; Lai, Cheng Yuan; Lin, Tzer Bin.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 294, No. 2, 02.2008.

Research output: Contribution to journalArticle

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AU - Peng, Mei Lin

AU - Wang, Pei Yi

AU - Lee, Shin Da

AU - Chang, Hung Ming

AU - Pan, Shwu Fen

AU - Chen, Mei Jung

AU - Tung, Kwong Chung

AU - Lai, Cheng Yuan

AU - Lin, Tzer Bin

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AB - Calcium/calmodulin protein kinase (CaMK)-dependent nitric oxide (NO) and the downstream intracellular messenger cGMP, which is activated by soluble guanylate cyclase (sGC), are believed to induce long-term changes in efficacy of synapses through the activation of protein kinase G (PKG). The aim of this study was to examine the involvement of the CaMKII-dependent NO/sGC/PKG pathway in a novel form of repetitive stimulation-induced spinal reflex potentiation (SRP). A single-pulse test stimulation (TS; 1/30 Hz) on the afferent nerve evoked a single action potential, while repetitive stimulation (RS; 1 Hz) induced a long-lasting SRP that was abolished by a selective Ca 2+/CaMKII inhibitor, autocamtide 2-related inhibitory peptide (AIP). Such an inhibitory effect was reversed by a relative excess of nitric oxide synthase (NOS) substrate, L-arginine. In addition, the RS-induced SRP was abolished by pretreatment with the NOS inhibitor, NG-nitro-L- arginine-methyl ester (L-NAME). The sGC activator, protoporphyrin IX (PPIX), reversed the blocking effect caused by L-NAME. On the other hand, a sGC blocker, 1H-[1, 2, 4]oxadiazolo[4, 3-α]quinoxalin-1-one (ODQ), abolished the RS-induced SRP. Intrathecal applications of the membrane-permeable cGMP analog, 8-bromoguanosine 3′,5′-cyclic monophosphate sodium salt monohydrate (8-Br-cGMP), reversed the blocking effect on the RS-induced SRP elicited by the ODQ. Our findings suggest that a CaMKII-dependent NO/sGC/PKG pathway is involved in the RS-induced SRP, which has pathological relevance to hyperalgesia and allodynia.

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