This family contains a number of eukaryotic Insulin-induced proteins (INSIG-1 and INSIG-2) approximately 200 residues long. INSIG-1 and INSIG-2 are found in the endoplasmic reticulum and bind the sterol-sensing domain of SREBP cleavage-activating protein (SCAP), preventing it from escorting SREBPs to the Golgi. Their combined action permits feedback regulation of cholesterol synthesis over a wide range of sterol concentrations [, ].The INSIG family also includes NSG1 and NSG2 (INSIG homologues 1 and 2) [].
This family includes the neuron-enriched endosomal proteins NSG1 (NEEP21), NSG2 (P19) and NSG3 (calcyon, Caly). They interact with distinct elements of the endosomal and synaptic scaffolding machinery []. NSG1 and NSG2 may not be resident endosomal proteins, and are also known as neuronal vesicle trafficking-associated proteins 1 and 2 respectively []. NSG1/NEEP21 plays a role in the trafficking of multiple receptors, including the cell adhesion molecule L1/NgCAM, the neurotransmitter receptor GluA2, and beta-APP []. The role of NSG2 is not known.It was originally thought that the Neuron-specific vesicular protein calcyon (previously known as D1 dopamine receptor-interacting, calcyon), interacted directly with the D1 dopamine receptor (DRD1) to modulate neocortical and hippocampal neuronal excitability as well as cAMP-dependent signalling []. However, this work was retracted, as it was shown that a direct interaction with the dopamine D1 receptor had been misinterpreted []. However, it has been shown that calcyon induces D1DR to stimulate intracellular Ca2+ release, and this suggests a possible functional interaction between calcyon and D1DR, despite there being, as yet, no direct interaction between them. A recent study suggested that calcyon-containing vesicles might transport D1DR by associating calcyon with D1DR through their assembly to clathrin []. However, as a single transmembrane protein, it is currently not clear how calcyon can regulate the internalization of D1DR from the plasma membrane to endocytic vesicles.Calcyon is a brain-specific protein, mainly localized in the intracellular endosomal vesicles of dendritic spines in dopamine expressing pyramidal cells in the prefrontal cortex and hippocampus and dorsal striatum region []. Neuron-specific vesicular protein calcyon has implicated in clathrin-mediated endocytosis. It is exclusively expressed in neurons, and localized in moving vesicles and it thought to play a role in brain plasticity []. Defective calcyon proteins have been implicated in both attention-deficit/hyperactivity disorder (ADHD) [, ]and schizophrenia [].
