Calmodulin kinase and a calmodulin-binding 'IQ' domain facilitate L-type Ca2+ current in rabbit ventricular myocytes by a common mechanism

Yuejin Wu, Igor Dzhura, Roger J. Colbran, Mark E. Anderson

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


1. Ca2+-calmodulin-dependent protein kinase II (CaMK) and a calmodulin (CaM)-binding 'IQ' domain (IQ) are both implicated in Ca2+-dependent regulation of L-type Ca2+ current (ICa). We used an IQ-mimetic peptide (IQmp), under conditions in which CaMK activity was controlled, to test the relationship between these CaM-activated signalling elements in the regulation of L-type Ca2+ channels (LTCCs) and ICa in rabbit ventricular myocytes. 2. A specific CaMK inhibitory peptide nearly abolished ICa facilitation, but the facilitation was 'rescued' by cell dialysis with IQmp. 3. IQmp significantly enhanced ICa facilitation and slowed the fast component of ICa inactivation, compared with an inactive control peptide. Neither effect could be elicited by a more avid CaM-binding peptide, suggesting that generalized CaM buffering did not account for the effects of IQmp. 4. ICa facilitation was abolished and the fast component of inactivation eliminated by ryanodine, caffeine or thapsigargin, suggesting that the sarcoplasmic reticulum (SR) is an important source of Ca2+ for ICa facilitation and inactivation. IQmp did not restore ICa facilitation under these conditions. 5. Engineered Ca2+-independent CaMK and IQmp each markedly increased LTCC open probability (Po) in excised cell membrane patches. The LTCC Po increases with CaMK and IQmp were non-additive, suggesting that CaMK and IQmp are components of a shared signalling pathway. 6. Both CaMK and IQmp induced a modal gating shift in LTCCs that favoured prolonged openings, indicating that CaMK and IQmp affect LTCCs through a common biophysical mechanism. 7. These findings support the hypothesis that CaMK is required for physiological ICa facilitation in cardiac myocytes. Both CaMK and IQmp were able to induce a modal gating shift in LTCCs, suggesting that each of these signalling elements is important for Ca2+-CaM-dependent LTCC facilitation in cardiac myocytes.

Original languageEnglish (US)
Pages (from-to)679-687
Number of pages9
JournalJournal of Physiology
Issue number3
StatePublished - Sep 15 2001
Externally publishedYes

ASJC Scopus subject areas

  • Physiology


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