That expression of the α
1F subunit depends on the expression of the β
2 subunit is analogous to the impact on the α
1S subunit when the β
1 subunit is inactivated.
17 In adults, skeletal muscle expresses a single VDCC composed of α
1S, α
2/δ, β
1, and γ
1 subunits. The loss of the α
1 subunits in both these cases results from a dependence on the β subunit for normal surface expression of the channel (see Ref.
16 for review). The underlying mechanism is not clearly understood, but the α
1/β interaction in the endoplasmic reticulum (ER) appears to mask an ER retention signal present on the α
1 subunit.
44 In contrast to these effects, studies of Schaffer collateral synapses in the hippocampus of β
4-null (
lethargic) mice indicate that loss of the β
4 subunit has little effect on the two main VDCCs at this synapse.
22 This indicates that, in contrast to skeletal muscle, other β subunits are expressed in these neurons and consequently are able to form pairings with α
1 subunits to produce functional channels. This process of alternate α
1/β subunit pairing has been referred to as subunit reshuffling.
21 McEnery et al.
45 showed that expression of the β
1b isoform was increased in several areas of the β
4-null mouse brain, which could explain the relatively mild effects of deleting this subunit. In β
3-null mice a significant decrease in the level of L- and N-type VDCCs was observed in sympathetic neurons in the superior cervical ganglion, indicating that the level of expression of the β subunits may have been limiting.
26 In light of these findings, the most likely explanation for the phenotype of the CNS-β
2–null mice is that the β
2 subunit is the predominant β subunit in photoreceptors, and the expression level of any other β subunit is insufficient to allow normal expression of the α
1F subunit at the ribbon synapse. Alternatively, if other β subunits are present, they are unable to pair with the α
1F subunit. Although possible, the latter explanation is unlikely, because large numbers of in vitro studies have examined α
1/β subunit pairings, and almost all combinations tested to date are able to produce functional channels.
16