Action potential

1
Cardiac Bioelectricity and Arrhythmia Center
(CBAC)
A computational model of ß-adrenergic signaling
in cardiac myocytes Local signaling and
rate-dependent action-potential effects
Jordi Heijman (1,2), Paul G.A. Volders (2),
Ronald L. Westra (2) and Yoram Rudy (1)
(1) Washington University, St. Louis, MO, USA
(2) Maastricht University, Maastricht, The
Netherlands Disclosures none (all authors)
Adrenergic electrophysiological characteristics
LQT1 local signaling
Block of IKs, mimicking LQT1 AKAP /
Channel disruption
ß-Adrenergic signaling characteristics Comparison
of the signaling model (solid lines) with
experimental data (markers) shows excellent
agreement

• Electrophysiological characteristics
• Adjusted electrophysiological properties for
  phosphorylated substrates
• IKs left-shift and increase in tail-current I-V
  relation, increased rate of activation, decreased
  rate of deactivation1,2
• ICaL increase and left-shift in peak I-V,
  left-shift of inactivation3

CL 2000 ms
CL 300 ms

• Volders et al., Circulation
• 2003. 280, 1808
• 2. Stengl et al., J. Physiol. 2003. 551, 777
• 3. Antoons et al., J. Physiol. 2007. 579, 147
• 4. Baba et al., Cardiovasc. Res. 2004. 64, 260
• 5. Odermatt et al., J. Biol. Chem. 1996. 271,
  14206
• 6. Robertson et al., J. Biol. Chem. 1982. 257,
  260

• IKs block has only a modest effect on APD under
  baseline conditions (i.e. without ISO)
• After ISO application APD increase under IKs
  block is much larger. This is most pronounced at
  slow rates

CL 2000 ms

• The IKs AKAP Yotiao provides passive regulation
  through local PKA and PP1 concentrations but is
  also critical for active phosphorylation

7. Kuschel et al., PNAS. 1974. 71, 3580 8.
Stengl et al., Cardiovasc. Res. 2006. 72, 90 9.
Nagykaldi et al., Am. J. Physiol. 2000. 279,
H1329 10. Gao et al., J. Physiol. 1992. 449, 689
11. Sulakhe and Vo., Mol. Cell. Biochem. 1995.
149, 103 12. Kirstein et al., Eur. J. Physiol.
1996. 431, 395
1. Chen-Goodspeed et al., J Biol. Chem. 2005.
280, 1808 2. Freedman et al., J. Biol. Chem.
1996. 270, 17953 3. Steinberg et al.,
Circulation. 1995. 4. Yu et al., Circulation.
2001. 102, 2535 5. Hohl and Li, Circ. Res. 1991.
69, 1369 6. Beavo et al., PNAS. 1974. 71, 3580

• Mutations that disrupt IKs / Yotiao interaction
  prevent phosphorylation of the IKs channel
• The model shows that this increases APD compared
  to normal ISO application, particularly in the
  case of complete IKs / Yotiao disruption

Action potential rate-dependence
AP and CaT morphology
Validation
APD Rate dependence APD rate dependence is
qualitatively similar to experimental results in
canine ventricular myocytes (using different
perfusate and pipette solutions)
CL 1000 ms
CL 300 ms
CL 1000 ms
CL 2000 ms
CL 2000 ms
CL 1000 ms
Stengl et al., J. Physiol. 2003. 551, 777
Charpentier et al., Am. J. Physiol. 1996. 271,
H1174
1. Yamada and Corr, J. Cardiovasc.
Electrophysiol. 1992. 3, 209 2. Waggoner et al.
,Am. J. Physiol. 2009. 296, H698

• Application of a saturating dose of ISO decreases
  APD, particularly at slow rates and increases CaT
  amplitude, most prominently at fast rates.
• AP morphology, CaT amplitude and rate of decay
  are in good agreement with experimental data

This work has been supported by Washington
University in St. Louis Cardiac Bioelectricity
and Arrhythmia Center and the NIH-NHLBI Grants
R37-HL33343 and RO1-HL49054. Financial support
from the Hein Wellens Foundation to J.H. is
gratefully acknowledged
http//rudylab.wustl.edu
http//cbac.wustl.edu