(i) The gating mechanism of voltage dependent ion channels will be investigated, and (ii) the distribution of voltage gated channels in central neurons. Voltage dependent ion channels underlay many processes that are essential to life, frog conductance of nerve impulses, to analysis of information in the brain, to timing of the heartbeat. These essential channels open and close ('gate') in response to voltage changes, and some of the elements of their ability to respond to voltage signals is inherent in the structure of the channel peptide. Gating is also sensitive to the divalent composition in the external solution. A major focus of this grant is to understand this sensitivity (which is medically important in hypocalcemia) and to understand the role of divalent cations in channels gating. Precise understanding of gating and the divalent cation effect will guide drug design. Voltage gated channels are essential to the function of all nerve cells of the brain, but relatively little is known of their distribution. A fundamental question is the channel composition of dendritic membrane, which determines the response of the dendrite, and the cell, to synaptic information. Do the cells respond to dendritic input by generating action potentials? Are the action potentials caused by Na channels, or Ca channels? It is time to begin extending our knowledge of voltage gated channels to these functional questions in neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS012547-20
Application #
2262446
Study Section
Physiology Study Section (PHY)
Project Start
1977-01-01
Project End
1998-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
20
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gomez-Lagunas, Froylan; Melishchuk, Alexey; Armstrong, Clay M (2003) Block of Shaker potassium channels by external calcium ions. Proc Natl Acad Sci U S A 100:347-51
Armstrong, Clay M (2003) The Na/K pump, Cl ion, and osmotic stabilization of cells. Proc Natl Acad Sci U S A 100:6257-62
Armstrong, C M; Cota, G (1999) Calcium block of Na+ channels and its effect on closing rate. Proc Natl Acad Sci U S A 96:4154-7
Armstrong, C M (1999) Distinguishing surface effects of calcium ion from pore-occupancy effects in Na+ channels. Proc Natl Acad Sci U S A 96:4158-63
Armstrong, C M; Hille, B (1998) Voltage-gated ion channels and electrical excitability. Neuron 20:371-80
Khodakhah, K; Melishchuk, A; Armstrong, C M (1998) Charge immobilization caused by modification of internal cysteines in squid Na channels. Biophys J 75:2821-9
Melishchuk, A; Loboda, A; Armstrong, C M (1998) Loss of shaker K channel conductance in 0 K+ solutions: role of the voltage sensor. Biophys J 75:1828-35
Khodakhah, K; Melishchuk, A; Armstrong, C M (1997) Killing K channels with TEA+. Proc Natl Acad Sci U S A 94:13335-8
Mathes, C; Rosenthal, J J; Armstrong, G M et al. (1997) Fast inactivation of delayed rectifier K conductance in squid giant axon and its cell bodies. J Gen Physiol 109:435-48
Khodakhah, K; Armstrong, C M (1997) Inositol trisphosphate and ryanodine receptors share a common functional Ca2+ pool in cerebellar Purkinje neurons. Biophys J 73:3349-57

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