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J Biol Chem, Vol. 273, Issue 34, 21435-21438, August 21, 1998

COMMUNICATION
Altered Expression and Assembly of N-type Calcium Channel _1B and  Subunits in Epileptic lethargic (lh/lh) Mouse

Maureen W. McEnery, Terry D. Copeland^¶, and Courtney L. Vance

From the  Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4970 and ^¶ ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, Maryland 21702

Voltage-dependent calcium channels (VDCC) are multisubunit complexes whose expression and targeting require the assembly of the pore-forming ₁ with auxiliary  and ₂/ subunits. The developmentally regulated expression and differential assembly of  isoforms with the _1B subunit to form N-type VDCC suggested a unique role for the 4 isoform in VDCC maturation (Vance, C. L., Begg, C. M., Lee, W.-L., Haase, H., Copeland, T. D., and McEnery, M. W. (1998) J. Biol. Chem. 273, 14495-14502). The focus of this study is the expression and assembly of _1B and  isoforms in the epileptic mouse, lethargic (lh/lh), a mutant anticipated to produce a truncated 4 subunit (Burgess, D. L., Jones, J. M., Meisler, M. H., and Noebels, J. L. (1997) Cell 88, 385-392). In this report, we demonstrate that neither full-length nor truncated 4 protein is expressed in lh/lh mice. The absence of 4 in lh/lh mice is associated with decreased expression of N-type VDCC in forebrain and cerebellum. The most surprising characteristic of the lh/lh mouse is increased expression of 1b protein. This result suggests a previously unidentified cellular mechanism wherein expression of the total pool of available  subunits is under tight metabolic regulation. As a consequence of increased 1b expression, the 1b is increased in its incorporation into _1B/ complexes relative to wild type. Thus, in striking similarity to the population of N-type VDCC present in immature rat brain, the population of N-type VDCC present in adult lh/lh mice is characterized by the absence of 4 with increased 1b expression and assembly into N-type VDCC. It is intriguing to speculate that the increased excitability and susceptibility to seizures observed in the lh/lh mouse arises from the inappropriate expression of an immature population of N-type VDCC throughout neuronal development.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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