N-type Ca2+ channels as scaffold proteins in the assembly of signaling molecules for GABAB receptor effects

Abstract

An emerging concept in signal transduction is the organization of neuronal receptors and channels into microdomains in which signaling proteins are brought together to regulate functional responses. With the multiplicity of potential protein-protein interactions arises the need for the regulation and timing of these interactions. We have identified N-type Ca2+ channel-signaling molecule complexes formed at different times upon activation of γ-aminobutyric acid, type B, receptors. The first type of interaction involves pre-association of signaling proteins such as Src kinase with the Ca2+ channel, because it is rapidly activated by the receptors and regulates the magnitude of the inhibition of the Ca2+ channel. The second type of interaction involves signaling molecules that are recruited to the channel by receptor activation and control the rate of the channel response. Recruitment of members of the Ras pathway has two effects as follows: 1) modulation of the rate of onset of the γ-aminobutyric acid-mediated inhibition of Ca2+ current, and 2) activation of MAP kinase. Our results suggest that the Ca2+ channel α1 subunit functions as a dynamic scaffold allowing assembly of intracellular signaling components that alter channel activity and route signals to the MAP kinase pathway.