Calmodulin mediates differential sensitivity of CaMKII and calcineurin to local Ca2+ in cardiac myocytes
Catherine
Lloyd
Auckland Bioengineering Institute, The University of Auckland
Model Status
This CellML model is known to run PCEnv. Because the model is in a CellML 1.1 format (as opposed to CellML 1.0) COR is unable to run the model. Where possible unit checking was carried out and to our knowledge they are consistent.
It should be noted that the paper does not provide values for [K], [Mg], and [Ca]. Correspondence with the author of the publication has provided values for these variables, namely; 135mM, 1mM and a value for Ca which is predicted dynamically from the Shannon et al. model (also in the CellML Model Respository). Unfortunately, the Ca concentration was calculated using a procedural command in the original Matlab code. We are currently working on a solution to this in the CellML model.
Model Structure
ABSTRACT: Calmodulin (CaM) mediates Ca-dependent regulation of numerous pathways in the heart including calmodulin-dependent kinase (CaMKII) and calcineurin (CaN), yet the local Ca(2+) signals responsible for their selective activation are unclear. To assess when and where CaM, CaMKII and CaN may be activated in the cardiac myocyte, we integrated new mechanistic computational models of CaM, CaMKII and CaN with the Shannon-Bers model of excitation-contraction coupling in the rabbit ventricular myocyte. These models are validated with independent in vitro data. In the intact myocyte, model simulations predict that CaM is highly activated in the dyadic cleft during each beat, but not appreciably in the cytosol. CaMKII-deltaC was almost insensitive to cytosolic Ca due to relatively low CaM affinity. Dyadic cleft CaMKII exhibits dynamic frequency-dependent responses to Ca yet autophosphorylates only when local phosphatases are suppressed. In contrast, dyadic cleft CaN in beating myocytes is predicted to be constitutively active, while the extremely high CaN affinity for CaM allows gradual integration of small cytosolic CaM signals. Reversing CaM affinities for CaMKII and CaN also reverses their characteristic local responses. Deactivation of both CaMKII and CaN seems dominated by Ca dissociation from the complex (vs. Ca-CaM dissociation from the target). In summary, the different affinities of CaM for CaMKII and CaN determine their sensitivity to local Ca signals in cardiac myocytes.
model diagram
Compartmental model schematic of cardiac myocyte EC coupling incorporating CaM, CaMKII, and CaN signalling in the dyadic cleft and cytosol.
model diagram
Reaction map for cooperative Ca binding of 2 Ca to CaM sequentially to the C-terminal and then N-terminal EF hands, along with binding of CaM buffers.
model diagram
Probabilistic model of CaMKIIδ subunit switching between inactive (Pi), inactive Ca2CaM bound (Pb2), active Ca4CaM-bound (Pb), Thr287 autophosphorylated with Ca4CaM trapped (Pt), and Thr287 autophosphorylated but CaM-autonomous (P) or CaCaM bound (P) states.
model diagram
Reaction map for reversible binding of CaM, CaCaM, and CaCaM to CaN.
The original paper reference is cited below:
Calmodulin mediates differential sensitivity of CaMKII and calcineurin to local Ca2+ in cardiac myocytes, Saucerman JJ, Bers DM, 2009, Biophysical Journal, 95, 4597-4612. PubMed ID: 18689454
JCaM_DYAD_SL
CaM transport between the dyadic space and the sarcolemma
JCa2CaM_DYAD_SL
Ca2CaM transport between the dyadic space and the sarcolemma
JCa4CaM_DYAD_SL
Ca4CaM transport between the dyadic space and the sarcolemma
JCaM_SL_CYT
CaM transport between the sarcolemma and the cytosol
JCa2CaM_SL_CYT
Ca2CaM transport between the sarcolemma and the cytosol
JCa4CaM_SL_CYT
Ca4CaM transport between the sarcolemma and the cytosol
The University of Auckland
Auckland Bioengineering Institute
keyword
electrophysiology
cardiac
myocyte
calcium dynamics
Auckland Bioengineering Institute
2008-11-15 00:00
2008-09-22T00:00:00+12:00
Biophysical Journal
18689454
Jeffery
Saucerman
J
Calmodulin Mediates Differential Sensitivity of CAMKII and Calcineurin to Local Ca2+ in Cardiac Myocytes
95
4597
4612
Donald
Bers
M
Catherine
Lloyd
May
c.lloyd@auckland.ac.nz