New study reveals essential molecules for neuromodulator secretion

Claudia Persoon (CNCR-FGA) and colleagues identified RAB3 and RIM1/2 as essential factors for neuromodulator secretion from dense core vesicles in mammalian neurons. This study is now published in Neuron.

In 1980, Novick and Schekman identified 23 proteins of the secretion pathway in Yeast. In the years following their breakthrough study, many of the yeast orthologs have been shown to have essential functions in synaptic vesicle exocytosis in the mammalian brain. Surprisingly, RAB3 proteins, orthologs of the essential yeast SEC4 protein, are not required for synaptic vesicle exocytsosis. Inactivation of all 4 RAB3 paralog genes in mice results in very subtle changes in synatic transmission (Schl├╝ter et al., 2004), but is lethal for the mice, suggesting RAB3 proteins have an unidentified essential function. This new study by Claudia Persoon, Rein Hoogstraten and Joris Nassal identifies RAB3 and RIM1/2 as essential proteins for neuromodulator release from dense core vesicles (DCVs) in mammalian neurons. The crucial role of RAB3 in this process shows the first distinct feature of DCV secretion compared to synaptic vesicle secretion, and identifies the essential function of RAB3 proteins.

Neuropeptides, neurotrophins and other signaling molecules (together neuromodulators) are secreted from DCVs and control many physiological functions as brain development, synaptic plasticity, circadian rhythm, behavior and emotions. Defects in neuromodulator signaling are associated with multiple psychiatric disorders, obesity and diabetes, but the mechanisms of neuromodulator secretion by DCVs is largely unknown. Inactivation of all four RAB3 genes resulted in an almost complete loss of DCV exocytosis, which was restored by re-expression of RAB3A. Conditional inactivation of RIM1/2 genes, known interactors of RAB3, resulted in an even greater loss of DCV exocytosis. The N-terminus of RIM1, which interacts with RAB3 and MUNC13, was sufficient to fully restore DCV fusion and travelled together with DCVs in a RAB3-dependent manner. Together, these data show that RIMs are essential interacting partners of RAB3 and organize DCV fusion by positioning MUNC13 and recruiting DCVs via RAB3.

The paper is published on October 31st in Neuron and is available here.