Altered Expression and Assembly of N-Type Calcium Channel Alpha(1b) and Beta Subunits in Epileptic Lethargic (Lh/Lh) Mouse

Voltage-dependent calcium channels (VDCC) are multisubunit complexes whose expression and targeting require the assembly of the pore-forming alpha(1) with auxiliary beta and alpha(2)/delta subunits, The developmentally regulated expression and differential assembly of beta isoforms with the cu,, subunit to form N-type VDCC suggested a unique role for the beta 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 alpha(1B) and beta isoforms in the epileptic mouse, lethargic (lh/lh), a mutant anticipated to produce a truncated beta 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 beta 4 protein is expressed in lh/lh mice. The absence of beta 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 beta 1b protein. This result suggests a previously unidentified cellular mechanism wherein expression of the total pool of available beta subunits is under tight metabolic regulation. As a consequence of increased beta 1b expression, the beta 1b is increased in its incorporation into alpha(1B)/beta 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 beta 4 with increased beta 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. [References: 33]

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