@misc {43143,
	title = {In silico Model of Gating Kinetics, Temperature Dependence and Calcium Sensitivity of the SK Channel},
	year = {2018},
	month = {09/2018},
	type = {Conference Poster},
	address = {Biophysical Society Thematic Meeting: The Heart by Numbers},
	abstract = {The small conductance calcium activated potassium (SK) channel affects atrial repolarization and is implicated in the onset and progression of atrial fibrillation (AF). In vitro, in vivo and genetic studies have provided functional and molecular links between SK channels and AF. SK inhibition promotes AF termination and protects against AF re-induction in large animal models, but the effect of SK modulation in humans remains limited and controversial.Objective: To provide a detailed computational SK model for interrogating the role of these channels in human atrial electrophysiology and arrhythmogenesis.Methods and Results: We have constructed a detailed Markov SK model from single channel and excised inside-out macropatch recordings. Single channel data confirmed the previously reported gating structure of neuronal SK2 channels (4 closed and 2 open states), and were used to define the transition kinetics for calcium-dependent SK activation. Inside-out macropatch recordings uncovered a strong temperature-dependence of SK Ca2+-sensitivity. At room temperature, the EC50 for hSK2 and hSK3 was 0.38 {\textpm} 0.02 {\textmu}M and 0.53 {\textpm} 0.07 {\textmu}M, respectively. Increasing the temperature to 37{\textdegree}C shifted SK Ca2+-sensitivity towards the diastolic range for both hSK2 and hSK3 (EC50 = 0.22 {\textpm} 0.01 {\textmu}M and 0.18 {\textpm} 0.02 {\textmu}M, respectively). The associated Q10 values were 1.44 (hSK2) and 2.05 (hSK3). \&nbsp;This temperature dependence will be incorporated into the Markovian formulation, which itself will be embedded in a human atrial myocyte model and tissue constructs, to assess the implications for SK channel function in vivo.Conclusions: The novel temperature dependence of SK channel Ca2+-sensitivity indicates partial channel activity during atrial diastole. This finding implies that SK channel localization may be less important than previously assumed, and that SK channels may be capable of modulating atrial resting potential and repolarization, particularly during calcium overload and AF.},
	author = {Ilsbeth Gerarda Ma {van Herck} and Bo H {Bentzen} and Seutin, Vincent and Koivum{\"a}ki, Jussi and Maleckar, Molly and Neil V {Marrion} and Andrew G {Edwards}}
}
@misc {43144,
	title = {Model development of SK channel gating incorporating calcium sensitivity and drug interaction},
	year = {2018},
	month = {02/2018},
	type = {Conference Poster},
	address = {Biophysical Society 62nd Annual Meeting, San Francisco CA},
	abstract = {Small conductance calcium activated potassium (SK) channels are predominantly expressed in heart atria and contribute to late repolarization of the action potential. Inhibition of SK current has been proposed as a therapy for atrial fibrillation (AF). We aim to develop an accurate model of SK channel gating and drug interaction that can be used to probe the role of SK channel in atrial health and disease.\&nbsp;The model, based on Hirschberg et al{\textquoteright}s (1998) SK2 model, incorporates 4 closed and 2 open states. To generate a model with utility at physiologic temperature, we performed inside-out macropatch voltage clamp ramps at 23{\textdegree} and 37{\textdegree}C, and observed a pronounced leftward EC50 shift at 37{\textdegree}C (0.53 {\textpm} 0.07\&nbsp;{\textmu}M and 0.38 {\textpm} 0.02\&nbsp;{\textmu}M to\&nbsp;0.23 {\textpm} 0.02\&nbsp;{\textmu}M and 0.28 {\textpm} 0.01\&nbsp;{\textmu}M for hSK3 and hSK2, respectively). Thus, taking calcium activation of the major hSK isoforms into the diastolic calcium range. To provide a first-principles basis for constraining the kinetics of multi-step calcium-dependent activation, and binding of known and novel pharmacologic inhibitors, we performed single0channel recordings of SK2 at 23{\textdegree}C. Opening events without inhibitors were best fit with two major open-state conductances (low: 10.9 {\textpm} 1.6 pS, 60 {\textpm} 41\% of events; high: 14.9 {\textpm} 1.4 pS, 40 {\textpm} 41\% of events), justifying the multiple open states included in the model and to be further analysed regarding state specific kinetics. We will also present single channel data on known inhibitor apamin and novel modulator AP14145 constraining a pharmacological model. In conclusion, these experiments provided novel findings on temperature sensitivity of SK channel. These will be incorporated into an improved Markov model of SK channel dynamics to elucidate the roles of SK channels in health and disease.\&nbsp;},
	author = {Ilsbeth Gerarda Ma {van Herck} and Bo H {Bentzen} and Seutin, Vincent and Arevalo, Hermenegild and Maleckar, Molly and Neil V {Marrion} and Andrew G {Edwards}}
}
@article {van2018model,
	title = {Model development of sk channel gating incorporating calcium sensitivity and drug interaction},
	journal = {Biophysical Journal},
	volume = {114},
	number = {3},
	year = {2018},
	pages = {306a},
	publisher = {{Elsevier},
	author = {van Herck, Ilse and Bo H {Bentzen} and Seutin, Vincent and Arevalo, Hermenegild and Maleckar, Molly and Neil V {Marrion} and Andrew G {Edwards}}
}
