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The role(s) of the novel stargazin-like gamma-subunit proteins remain controversial. We have shown previously that the neuron-specific gamma7 suppresses the expression of certain calcium channels, particularly Ca(V)2.2, and is therefore unlikely to operate as a calcium channel subunit. We now show that the effect of gamma7 on Ca(V)2.2 expression is via an increase in the degradation rate of Ca(V)2.2 mRNA and hence a reduction of Ca(V)2.2 protein level. Furthermore, exogenous expression of gamma7 in PC12 cells also decreased the endogenous Ca(V)2.2 mRNA level. Conversely, knockdown of endogenous gamma7 with short-hairpin RNAs produced a reciprocal enhancement of Ca(V)2.2 mRNA stability and an increase in endogenous calcium currents in PC12 cells. Moreover, both endogenous and expressed gamma7 are present on intracellular membranes, rather than the plasma membrane. The cytoplasmic C terminus of gamma7 is essential for all its effects, and we show that gamma7 binds directly via its C terminus to a heterogeneous nuclear ribonucleoprotein (hnRNP A2), which also binds to a motif in Ca(V)2.2 mRNA, and is associated with native Ca(V)2.2 mRNA in PC12 cells. The expression of hnRNP A2 enhances Ca(V)2.2 I(Ba), and this enhancement is prevented by a concentration of gamma7 that alone has no effect on I(Ba). The effect of gamma7 is selective for certain mRNAs because it had no effect on alpha2delta-2 mRNA stability, but it decreased the mRNA stability for the potassium-chloride cotransporter, KCC1, which contains a similar hnRNP A2 binding motif to that in Ca(V)2.2 mRNA. Our results indicate that gamma7 plays a role in stabilizing Ca(V)2.2 mRNA.

Original publication

DOI

10.1523/JNEUROSCI.2709-08.2008

Type

Journal article

Journal

J Neurosci

Publication Date

15/10/2008

Volume

28

Pages

10604 - 10617

Keywords

Animals, COS Cells, Calcium Channels, Calcium Channels, N-Type, Cells, Cultured, Cercopithecus aethiops, Female, GTP-Binding Protein gamma Subunits, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Humans, PC12 Cells, Protein Subunits, RNA Stability, RNA, Messenger, RNA-Binding Proteins, Rats, Xenopus