Burgess DL, Biddlecome GH, McDonough SI, Diaz ME, Zilinski CA, Bean BP, Campbell KP, Noebels JL

Neuronal voltage-dependent Ca2+ channels are heteromultimers of alpha1, beta, and alpha2delta subunits, and any one of five alpha1 subunits (alpha1A-E) may associate with one of four beta subunits (beta1-4). The specific alpha1-beta combination assembled determines single-channel properties, while variation in the proportion of each combination contributes to the functional diversity ...

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of neurons. The mouse mutant lethargic (lh) exhibits severe neurological defects due to a mutation that deletes the alpha1 subunit interaction domain of the beta4 subunit. Since beta subunits regulate critical alpha1 subunit properties in heterologous expression systems, loss of beta4 in lethargic could dramatically alter channel localization and behavior unless beta1-3 subunits can be used as substitutes in vivo. Here we demonstrate increased steady-state associations of alpha1A and alpha1B with the remaining beta1-3 subunits, without significant changes in beta1-3 mRNA abundance. The immunolocalization of alpha1A and alpha1B protein in lethargic brain is indistinguishable from wild-type by light microscopy. Furthermore, the measurement of large-amplitude P-type currents in dissociated lethargic Purkinje neurons indicates that these alpha1A-containing channels retain regulation by beta subunits. We conclude that several properties of alpha1A and alpha1B proteins are not uniquely regulated by beta4 in vivo and may be rescued by beta1-3 subunit reshuffling. The complex neurological manifestation of the lethargic mutation therefore emerges from loss of beta4 coupled with the widespread pairing of surrogate beta subunits with multiple Ca2+ channel subtypes. The existence of beta subunit reshuffling demonstrates that molecular plasticity of Ca2+ channel assembly, a normal feature of early brain development, is retained in the mature brain.

Date: Apr. 01, 1999

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