Ågren R , Nilsson J , Århem P .

	Figure 1. Implications of differential state-dependent Kv channel block on the firing pattern. (A) Spiking patterns at 5.3 and 5.6 mA/m2 assuming no drug or 200 μM (corresponding to 1 Kd concentration) on a closed state binding model (red) and an open state binding model (blue). (B) Potassium channel closing (αn+2βn) and blocking rates (Lo · κ + λ) for 1–4 Kd equivalents as functions of membrane potential. (C) Potassium channel state fractions OK3 (black), CB (red) and OB (blue) at 5.3 and 5.6 mA/m2 assuming no drug or 200 μM (corresponding to a concentration of 1 Kd equivalent) on a closed state binding model and an open state binding model. Insets for the open state binding model demonstrate the accumulation of OB over time. (D) Number of action potentials (above −10 mV) during 60 ms at 5.1–6.0 mA/m2 stimulation for 0–800 μM (corresponding to 0–4 Kd equivalents) on a closed state binding model and an open state binding model. (E) Peak width of first action potential at −10 mV at 5.1–6.0 mA/m2 stimulation for 0–800 μM (corresponding to 0–4 Kd equivalents) on a closed state binding model and an open state binding model.
	Figure 2. Normalized Ca influx for closed state and open state binding of Kv blocking drug. (A) Normalized Ca currents at 5.3 and 5.6 mA/m2 assuming no drug (black) or 200 μM (corresponding to 1 Kd concentration) on a closed-state binding model (red) and an openstate binding model (blue). (B) Normalized Ca integral at 5.1–6.0 mA/m2 stimulation for 0–800 μM (corresponding to 0–4 Kd equivalents; Kd = 200 μM) drug concentration for the closed state and open state binding cases.
	Figure 3. Normalized calcium integrals for different stimulations depending on the affinity of the resting and the open state for a Kv specific drug. Stimulations from 5.3 to 5.9 mA/m2. Drug concentrations from 0–480 μM (corresponding to 0–2.4 Kd). The dominant effect is that of an increased normalized calcium integral (>1).
	Figure 4. Markov model of Nav channel derived from the Frankenhaeuser-Huxley model. CNaj, ONaj and INaj represent closed, open and inactivated channel states and αj and βj voltage-dependent rate constants.
	Figure 5. Markov model of Kv channel derived from the Frankenhaeuser-Huxley model with introduced closed and open blocked states, CB and OB. αj and βj denote voltage-dependent rate constants. κ and λ denote binding rate constants, LC and LO the concentration of the closed and open state blocking agent respectively.
	Figure 6. N-type Cav channel model derived from Patil et al. CCaj, OCaj and ICaj represent closed, open and inactivated states, kij rate constants.

Arhem, Mechanisms of anesthesia: towards integrating network, cellular, and molecular level modeling. 2003, Pubmed

Arhem, Mechanisms of anesthesia: towards integrating network, cellular, and molecular level modeling. 2003, Pubmed
Armstrong, A model for 4-aminopyridine action on K channels: similarities to tetraethylammonium ion action. 2001, Pubmed
Armstrong, The inner quaternary ammonium ion receptor in potassium channels of the node of Ranvier. 1972, Pubmed
Boland, Modulation of N-type calcium channels in bullfrog sympathetic neurons by luteinizing hormone-releasing hormone: kinetics and voltage dependence. 1993, Pubmed
Bouchard, Closed- and open-state binding of 4-aminopyridine to the cloned human potassium channel Kv1.5. 1995, Pubmed
Cramer, Kainic acid and 4-aminopyridine seizure models in mice: evaluation of efficacy of anti-epileptic agents and calcium antagonists. 1994, Pubmed
Ellinwood, In Silico Assessment of Efficacy and Safety of IKur Inhibitors in Chronic Atrial Fibrillation: Role of Kinetics and State-Dependence of Drug Binding. 2017, Pubmed
Ellinwood, Revealing kinetics and state-dependent binding properties of IKur-targeting drugs that maximize atrial fibrillation selectivity. 2017, Pubmed
FRANKENHAEUSER, THE ACTION POTENTIAL IN THE MYELINATED NERVE FIBER OF XENOPUS LAEVIS AS COMPUTED ON THE BASIS OF VOLTAGE CLAMP DATA. 1964, Pubmed , Xenbase
Feng, Ionic mechanisms of regional action potential heterogeneity in the canine right atrium. 1998, Pubmed
Goldman, POTENTIAL, IMPEDANCE, AND RECTIFICATION IN MEMBRANES. 1943, Pubmed
Imredy, Energetic and structural interactions between delta-dendrotoxin and a voltage-gated potassium channel. 2000, Pubmed , Xenbase
Juhng, Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-K(alpha) and pandinustoxin-K(alpha). 1999, Pubmed
Kocsis, Functional differences between 4-aminopyridine and tetraethylammonium-sensitive potassium channels in myelinated axons. 1987, Pubmed
Lenz, Dofetilide, a new class III antiarrhythmic agent. 2000, Pubmed
Long, Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. 2005, Pubmed
MacNeil, The side effect profile of class III antiarrhythmic drugs: focus on d,l-sotalol. 1997, Pubmed
Mouhat, Animal toxins acting on voltage-gated potassium channels. 2008, Pubmed
Newitt, Potassium channels and epilepsy: evidence that the epileptogenic toxin, dendrotoxin, binds to potassium channel proteins. 1991, Pubmed , Xenbase
Nilsson, Bupivacaine blocks N-type inactivating Kv channels in the open state: no allosteric effect on inactivation kinetics. 2008, Pubmed , Xenbase
Nilsson, Local anesthetic block of Kv channels: role of the S6 helix and the S5-S6 linker for bupivacaine action. 2003, Pubmed , Xenbase
Patil, Preferential closed-state inactivation of neuronal calcium channels. 1998, Pubmed
Rho, Developmental seizure susceptibility of kv1.1 potassium channel knockout mice. 1999, Pubmed
Rosati, Regional variation in mRNA transcript abundance within the ventricular wall. 2006, Pubmed
Tateno, Threshold firing frequency-current relationships of neurons in rat somatosensory cortex: type 1 and type 2 dynamics. 2004, Pubmed
Valenzuela, Stereoselective block of cardiac sodium channels by bupivacaine in guinea pig ventricular myocytes. 1995, Pubmed
Voskuyl, Spontaneous epileptiform discharges in hippocampal slices induced by 4-aminopyridine. 1985, Pubmed
White, Bites and stings from venomous animals: a global overview. 2000, Pubmed
Yeh, Immobilisation of gating charge by a substance that simulates inactivation. 1978, Pubmed
Yu, The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. 2004, Pubmed
Zeberg, Ion channel density regulates switches between regular and fast spiking in soma but not in axons. 2010, Pubmed , Xenbase
Zhou, Markov models of use-dependence and reverse use-dependence during the mouse cardiac action potential. 2012, Pubmed