Abstract
In the striatum, signaling via G protein-coupled neurotransmitter receptors is essential for motor control. Critical to this process is the effector enzyme adenylyl cyclase type 5 (AC5) that produces second messenger cAMP upon receptor-mediated activation by G protein Golf. However, the molecular organization of the Golf-AC5 signaling axis is not well understood. In this study, we report that in the striatum AC5 exists in a stable pre-coupled complex with subunits of Golf heterotrimer. We use genetic mouse models with disruption in individual components of the complex to reveal hierarchical order of interactions required for AC5-Golf stability. We further identify that the assembly of AC5-Golf complex is mediated by PhLP1 chaperone that plays central role in neurotransmitter receptor coupling to cAMP production motor learning. These findings provide evidence for the existence of stable G protein-effector signaling complexes and identify a new component essential for their assembly.
Highlights
Neurotransmitters elicit their effects by activating receptors on the surface of neurons
In this study we demonstrate that adenylyl cyclase type 5 (AC5), the key cyclic adenosine monophosphate (cAMP)-producing enzyme in the striatum, forms stable complexes with its regulatory G protein species Gaolfb2g7 in vivo
We further demonstrate that binding to Gaolfb2g7 complex is required for the proteolytic stabilization of AC5 that results in its high expression level in the striatum
Summary
Neurotransmitters elicit their effects by activating receptors on the surface of neurons. G proteincoupled receptors (GPCRs) form the largest group of the receptors responsible for the actions of the majority of neurotransmitters and play a critical role in virtually all neuronal functions (Gainetdinov et al, 2004; Wettschureck and Offermanns, 2005). Upon binding to neurotransmitter, GPCRs undergo conformational changes activating heterotrimeric G proteins by promoting GTP binding to Ga subunits and triggering the release of the Gbg subunits. When dissociated, both Ga and Gbg subunits modulate the activities of downstream effector molecules that are directly responsible for generating cellular responses (Gilman, 1987; Neer, 1995)
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