Voltage grated Ca2+ channels control entry of Ca2+ into cells under physiologic and pathologic conditions. They are targets of a major class of hypertension controlling drugs, they are targets of autoimmune reactions that lead to cell death as may happen in rare diseases such as amyotrophic lateral sclerosis as well as in more frequent diseases such as type I diabetes. An understanding of their diversity, their complexity and their functioning is of central importance.
The aim of the research is to relate structural elements of the alpha1 and beta subunits of Ca2+ channels to their functional properties. The basic tools to be used are the construction via recombinant DNA techniques of mutant and chimeric molecules and the measurement of their interaction and properties upon expression in Xenopus oocytes. The expectation that positive information will be obtained through these manipulations is based on 1. the acquisition through molecular cloning on our part of two homologous alpha1 cDNA's, type C and type E, that have distinguishing electrophysiological and pharmacological properties and can be expressed well in Xenopus oocytes; 2. the acquisition through molecular cloning on our part of several beta subunit cDNA's that can also be expressed in Xenopus oocytes and of which some impart distinguishing properties to the alpha1 subunits when co-expressed in Xenopus oocytes; and 3. the association through collaboration of the PI with Dr. Enrico Stefani, who will carry out a thorough and insightful analysis of the electrophysiological properties of the constructed molecules.
Specific aims center on the elucidation through construction of chimeras of the major structure-function relations for alpha1 in an attempt to determine those structures required for Ca2+ inactivation of some but not others, for voltage inactivation, for regulation by phosphorylation and for key pharmacologic properties. The application is submitted as part of an Investigator-initiated Research Project Grant (IRPG). The companion grant is Dr. Stefani's type II renewal application AR-38970. Results from these studies may contribute to the design of better therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR043411-01
Application #
2083127
Study Section
General Medicine B Study Section (GMB)
Project Start
1994-08-01
Project End
1999-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Platano, D; Qin, N; Noceti, F et al. (2000) Expression of the alpha(2)delta subunit interferes with prepulse facilitation in cardiac L-type calcium channels. Biophys J 78:2959-72
Qin, N; Olcese, R; Bransby, M et al. (1999) Ca2+-induced inhibition of the cardiac Ca2+ channel depends on calmodulin. Proc Natl Acad Sci U S A 96:2435-8
Birnbaumer, L; Qin, N; Olcese, R et al. (1998) Structures and functions of calcium channel beta subunits. J Bioenerg Biomembr 30:357-75
Qin, N; Olcese, R; Stefani, E et al. (1998) Modulation of human neuronal alpha 1E-type calcium channel by alpha 2 delta-subunit. Am J Physiol 274:C1324-31
Ottolia, M; Platano, D; Qin, N et al. (1998) Functional coupling between human E-type Ca2+ channels and mu opioid receptors expressed in Xenopus oocytes. FEBS Lett 427:96-102
Costantin, J L; Qin, N; Zhou, J et al. (1998) Long lasting facilitation of the rabbit cardiac Ca2+ channel: correlation with the coupling efficiency between charge movement and pore opening. FEBS Lett 423:213-7
Costantin, J; Noceti, F; Qin, N et al. (1998) Facilitation by the beta2a subunit of pore openings in cardiac Ca2+ channels. J Physiol 507 ( Pt 1):93-103
Qin, N; Platano, D; Olcese, R et al. (1998) Unique regulatory properties of the type 2a Ca2+ channel beta subunit caused by palmitoylation. Proc Natl Acad Sci U S A 95:4690-5
Qin, N; Platano, D; Olcese, R et al. (1997) Direct interaction of gbetagamma with a C-terminal gbetagamma-binding domain of the Ca2+ channel alpha1 subunit is responsible for channel inhibition by G protein-coupled receptors. Proc Natl Acad Sci U S A 94:8866-71
Tareilus, E; Roux, M; Qin, N et al. (1997) A Xenopus oocyte beta subunit: evidence for a role in the assembly/expression of voltage-gated calcium channels that is separate from its role as a regulatory subunit. Proc Natl Acad Sci U S A 94:1703-8

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