title: Two candidates at the heart of dysfunction: The ryanodine receptor and calcium/calmodulin protein kinase II as potential targets for therapeutic intervention-An in vivo perspective.
abstract: At the start of a new decade (2011), heart failure and sudden cardiac death are still leading causes of mortality worldwide. There is a very obvious need for improved treatment strategies. Research over the past decade has focused on understanding and realising the therapeutic potential of molecular mechanisms that underlie the pathophysiology of cardiac dysfunction. There is now recognition that cell- and gene-based therapies could prove beneficial if aimed at the appropriate molecular targets. Two cardiac proteins that have received considerable attention over the last decade, have been identified as possible therapeutic targets. The cardiac sarcoplasmic reticulum Ca(2+) release channel (ryanodine receptor) and calcium/calmodulin dependent kinase II (CaMKIIδ) can act independently and in partnership, to regulate cardiac Ca(2+) handling. CaMKIIδ, by the very nature of its core function as a kinase, also modulates cardiac function globally, promoting effects on gene transcription and modulating inflammatory and proliferative responses, all events that are associated with both the functional and dysfunctional heart. In vivo approaches using genetic and pharmacologic strategies have revealed the prominent role of both proteins in cardiac dysfunction. More excitingly, they have also shown the potential for cardioprotection that modulation at the level of each protein can have. Translating these effects to the human heart is in its infancy. Whether intervention at these targets could result in clinical application is unknown at present, however current in vivo research has proved invaluable in revealing the potential that targeting of RyR and CaMKIIδ could have in limiting cardiac dysfunction.
authors.affiliation: Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 ONR, UK. susan.currie@strath.ac.uk
authors.forename: Susan
authors.initials: S
authors.lastname: Currie
authors.forename: Elspeth B
authors.initials: EB
authors.lastname: Elliott
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Loughrey
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005424:Flecainide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006331:Heart Diseases / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D013841:Thiazepines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; C540746:S-107 compound; D013841:Thiazepines; C109183:K201 compound; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005424:Flecainide; D002118:Calcium