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Title page for ETD etd-11132006-143811

Type of Document Dissertation
Author Grueter, Chad Eric
Author's Email Address chad.grueter@vanderbilt.edu
URN etd-11132006-143811
Title Ca2+/calmodulin-dependent protein kinase II regulates cardiac l-type Ca2+ channels via the beta subunit
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Jackie Corbin Committee Chair
Daniel Liebler Committee Member
Danny Winder Committee Member
John Exton Committee Member
Kevin Currie Committee Member
  • Protein kinases -- Physiological effect
  • Heart -- Physiology
  • Calcium
  • Cardiac
  • ion channels
  • kinase
  • signal transduction
  • Calmoduin
  • Calcium channels
Date of Defense 2006-10-19
Availability unrestricted
Heart disease is the number one cause of death in the United States. There are many forms of heart disease including heart failure and arrhythmias. One underlying theme in heart disease and many other diseases is disrupted Ca2+ homeostasis. Calcium is a charge carrier and universal mediator of diverse cellular processes. In cardiac myocytes, these processes include excitation-contraction coupling, gene transcription and apoptosis.

Ca2+ enters cardiac myocytes through L-type Ca2+ channels (LTCC) where it activates signaling molecules such as the multifunctional Ca2+/calmodulin dependent protein kinase II (CaMKII). CaMKII is one of many specialized proteins poised to respond to Ca2+ signaling in cardiac myocytes. Accumulating evidence links cardiac CaMKII activity to normal physiological regulation of several heart functions and to multiple pathological conditions.

CaMKII is associated with cardiac LTCC complexes and increases channel open probability (PO) to dynamically increase Ca2+ current (ICa) and augment cellular Ca2+ signaling by a process called facilitation. I found that activated CaMKII binds to the LTCC b2a subunit close to a preferred CaMKII phosphorylation site, Thr498 and colocalizes with b2a in cardiomyocytes. Mutation of Thr498 to Ala (T498A) in b2a prevents CaMKII-mediated increases in the PO of recombinant LTCCs. Moreover, expression of b2a (T498A) in adult cardiomyocytes ablates CaMKII-mediated ICa facilitation, demonstrating that phosphorylation of b2a at Thr498 modulates native Ca2+ channels.

In addition, I showed that binding requires CaMKII activation but phosphorylation at Thr498 inhibits binding. The b2a subunit also modulates CaMKII activity and enhances CaMKII autophosphorylation at a site other than Thr287 or Thr305/306. Analysis of the primary sequences of the four b isoforms reveal that the CaMKII binding/regulatory site is conserved in b1b but not in b3 nor b4 and CaMKII was shown to interact with b1b in a similar manner as b2a.

Taken together these findings reveal a novel molecular mechanism for dynamic targeting of CaMKII to LTCCs and facilitating ICa that may modulate Ca2+ entry in diverse cell types co-expressing CaMKII and the b2a subunit. Future work based on these findings may identify a potential pharmacological target for the treatment of heart disease or other pathological conditions involving disrupted Ca2+ homeostasis.

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