While synaptic vesicles in axonal terminals fuse with high reliability upon cell spiking, dendritic LDCV fusion requires sustained Ca2+ elevation, Apoptosis Compound Library cell line and the actual fusion events are not tightly time locked to cell firing (Xia et al., 2009). Ca2+ release from intracellular stores by thapsigargin treatment or by oxytocin is sufficient to induce LDCV exocytosis and promotes priming of the releasable pool of LDCVs in dendrites. However, these treatments have no effect on axonal release (Ludwig et al., 2002 and Tobin et al., 2004). Pretreatment with either oxytocin or thapsigargin enhances subsequent activity-triggered release of oxytocin supporting a feedforward mechanism of oxytocin release through binding of the Gq-coupled oxytocin

receptor and subsequent activation of phospholipase-C and Ca2+ release from ER stores. This feedforward enhancement lasts for tens of minutes, suggesting that it is a form of plasticity that transiently lowers selleck screening library the threshold for peptide release (Tobin et al., 2004). Dynorphin peptide exocytosis is another example where axonal and dendritic release is differentially regulated. Dynorphin is secreted from

hippocampal granule cell dendrites and acts retrogradely through presynaptic κ-opioid receptors to inhibit neurotransmitter vesicle release from perforant path terminals (Drake et al., 1994). Dynorphin-mediated depression at perforant path synapses is blocked by both N-type and L-type Ca2+ receptor antagonists, but only N-type inhibitors block axonal release of dynorphin, demonstrating a distinct MYO10 role for L-type Ca2+ channels in dendritic exocytosis (Simmons et al., 1995). The differential activity requirements for dendritic versus axonal release is a common theme in various subtypes of peptide-secreting neurons and suggests the presence of distinct dendritic release machinery that can respond to Ca2+ from different sources to trigger vesicle release. However, the release machinery,

including the complete cast of SNARE proteins and Ca2+ sensors in dendrites and axons of peptidergic neurons, remains to be identified. Neurons are polarized cells with typically one axon housing the molecular machinery for neurotransmitter release and several dendrites containing receptors and signaling molecules necessary to respond to neurotransmitter. How neuronal polarity is established and how molecules are sorted, delivered, and retained in neuronal subdomains remain central questions in cellular neurobiology (Barnes and Polleux, 2009). From the first steps of neurite outgrowth to maturity, the total membrane surface area of neurons can increase by several orders of magnitude, requiring massive amounts of membrane synthesis and mobilization to growing dendritic and axonal processes. Disruption of the endoplasmic reticulum (ER)-Golgi secretory pathway in developing neurons using pharmacologic or genetic methods prevents dendritic outgrowth in both mammals and insects (Horton et al., 2005 and Ye et al.