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1.  A Computational Investigation of Cardiac Caveolae as a Source of Persistent Sodium Current 
Recent studies of cholesterol-rich membrane microdomains, called caveolae, reveal that caveolae are reservoirs of “recruitable” sodium ion channels. Caveolar channels constitute a substantial and previously unrecognized source of sodium current in cardiac cells. In this paper we model for the first time caveolar sodium currents and their contributions to cardiac action potential morphology. We show that the β-agonist-induced opening of caveolae may have substantial impacts on peak overshoot, maximum upstroke velocity, and ultimately conduction velocity. Additionally, we show that prolonged action potentials and the formation of potentially arrhythmogenic afterdepolarizations, can arise if caveolae open intermittently throughout the action potential. Our simulations suggest that caveolar sodium current may constitute a route, which is independent of channelopathies, to delayed repolarization and the arrhythmias associated with such delays.
PMCID: PMC3229093  PMID: 22144962
caveolae; cardiomyocyte; caveolin-3; mathematical model; β-adrenergic; LQT9
2.  Voltage-gated Nav channel targeting in the heart requires an ankyrin-G–dependent cellular pathway 
The Journal of Cell Biology  2008;180(1):173-186.
Voltage-gated Nav channels are required for normal electrical activity in neurons, skeletal muscle, and cardiomyocytes. In the heart, Nav1.5 is the predominant Nav channel, and Nav1.5-dependent activity regulates rapid upstroke of the cardiac action potential. Nav1.5 activity requires precise localization at specialized cardiomyocyte membrane domains. However, the molecular mechanisms underlying Nav channel trafficking in the heart are unknown. In this paper, we demonstrate that ankyrin-G is required for Nav1.5 targeting in the heart. Cardiomyocytes with reduced ankyrin-G display reduced Nav1.5 expression, abnormal Nav1.5 membrane targeting, and reduced Na+ channel current density. We define the structural requirements on ankyrin-G for Nav1.5 interactions and demonstrate that loss of Nav1.5 targeting is caused by the loss of direct Nav1.5–ankyrin-G interaction. These data are the first report of a cellular pathway required for Nav channel trafficking in the heart and suggest that ankyrin-G is critical for cardiac depolarization and Nav channel organization in multiple excitable tissues.
PMCID: PMC2213608  PMID: 18180363
3.  Dihydropyridine Action on Voltage-dependent Potassium Channels Expressed in Xenopus Oocytes  
The Journal of General Physiology  1997;109(2):169-180.
Dihydropyridines (DHPs) are well known for their effects on L-type voltage-dependent Ca2+ channels. However, these drugs also affect other voltage-dependent ion channels, including Shaker K+ channels. We examined the effects of DHPs on the Shaker K+ channels expressed in Xenopus oocytes. Intracellular applications of DHPs quickly and reversibly induced apparent inactivation in the Shaker K+ mutant channels with disrupted N- and C-type inactivation. We found that DHPs interact with the open state of the channel as evidenced by the decreased mean open time. The DHPs effects are voltage-dependent, becoming more effective with hyperpolarization. A model which involves binding of two DHP molecules to the channel is consistent with the results obtained in our experiments.
PMCID: PMC2220064  PMID: 9041446
potassium channels; dihydropyridines

Results 1-3 (3)