Voltage-dependent calcium channels are present in all nerve and muscle cells. In heart muscle, calcium entry through voltage- dependent calcium channels triggers contraction. In neurons, calcium entry through presynaptic calcium channels plays multiple roles, including triggering release of neurotransmitter. Calcium channels in cardiac muscle and neurons can be modulated by the action of neurotransmitters and hormones. The proposed work will investigate mechanisms by which neurotransmitters modulate voltage- dependent calcium channels in cardiac myocytes and in hippocampal neurons. Patch clamp techniques will be used to study the control of calcium channels in cardiac myocytes by beta-adrenergic stimulation, using coordinated measurements of whole cell current, gating current, and single channel current. Cloned calcium channels in heterologous expression systems will be used to explore in detail how voltage-dependent gating steps are controlled by phosphorylation of the channel. The control of calcium channels by beta-adrenergic stimulation will be also studied in hippocampal CA3 and granule neurons. The types of calcium channels subject to beta- adrenergic modulation will be identified using selective toxins. The alteration of voltage-dependent gating properties of the channels will be characterized, and the consequences for control of the firing properties of the neurons will be explored. Using cardiac muscle, hippocampal neurons, and cloned channels, the mechanisms underlying potentiated channel activity induced by strong depolarizations will be studied. The physiological significance of this potentiation during action potentials in cardiac muscle and neurons will be evaluated. Neurotransmitter control of calcium channels is a basic process for the normal operation of the heart and the brain. Understanding the mechanisms involved will help understand pathological states such as cardiac arrhythmias, cardiac failure, stroke, and epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035034-18
Application #
6183060
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Baughman, Robert W
Project Start
1985-04-01
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
18
Fiscal Year
2000
Total Cost
$348,821
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
McDonough, Stefan I; Mori, Yasuo; Bean, Bruce P (2005) FPL 64176 modification of Ca(V)1.2 L-type calcium channels: dissociation of effects on ionic current and gating current. Biophys J 88:211-23
Blair, Nathaniel T; Bean, Bruce P (2003) Role of tetrodotoxin-resistant Na+ current slow inactivation in adaptation of action potential firing in small-diameter dorsal root ganglion neurons. J Neurosci 23:10338-50
Mitterdorfer, Jorg; Bean, Bruce P (2002) Potassium currents during the action potential of hippocampal CA3 neurons. J Neurosci 22:10106-15
Blair, Nathaniel T; Bean, Bruce P (2002) Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J Neurosci 22:10277-90
McDonough, Stefan I; Boland, Linda M; Mintz, Isabelle M et al. (2002) Interactions among toxins that inhibit N-type and P-type calcium channels. J Gen Physiol 119:313-28
Greif, G J; Sodickson, D L; Bean, B P et al. (2000) Altered regulation of potassium and calcium channels by GABA(B) and adenosine receptors in hippocampal neurons from mice lacking Galpha(o). J Neurophysiol 83:1010-8
Sodickson, D L; Bean, B P (1998) Neurotransmitter activation of inwardly rectifying potassium current in dissociated hippocampal CA3 neurons: interactions among multiple receptors. J Neurosci 18:8153-62
Raman, I M; Bean, B P (1997) Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons. J Neurosci 17:4517-26
McDonough, S I; Mintz, I M; Bean, B P (1997) Alteration of P-type calcium channel gating by the spider toxin omega-Aga-IVA. Biophys J 72:2117-28
McDonough, S I; Lampe, R A; Keith, R A et al. (1997) Voltage-dependent inhibition of N- and P-type calcium channels by the peptide toxin omega-grammotoxin-SIA. Mol Pharmacol 52:1095-104

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