Dendritic Release of Neurotransmitters

Abstract

Release of neuroactive substances by exocytosis from dendrites is surprisingly widespread and is not confined to a particular class of transmitters: it occurs in multiple brain regions, and includes a range of neuropeptides, classical neurotransmitters, and signaling molecules, such as nitric oxide, carbon monoxide, ATP, and arachidonic acid. This review is focused on hypothalamic neuroendocrine cells that release vasopressin and oxytocin and midbrain neurons that release dopamine. For these two model systems, the stimuli, mechanisms, and physiological functions of dendritic release have been explored in greater detail than is yet available for other neurons and neuroactive substances. © 2017 American Physiological Society. Compr Physiol 7:235-252, 2017.

Figure 1. Comparison of the mechanisms of somatodendritic release of oxytocin and vasopressin in the hypothalamus (A) and dopamine in the substantia nigra (B)

A) Neuropeptides are synthesized and packaged in the soma and stored in dendrites in a reserve pool (RP) containing large numbers of LDCVs in dendrites. Depolarization-induced Ca²⁺ entry through voltage-gated calcium channels (VGCCs) stimulates peptide release by exocytosis of LDCVs. This requires the depolymerization of F-actin to G-actin. Furthermore, the stimulation of G-protein coupled receptors, such as the oxytocin receptor, stimulates the mobilization of Ca²⁺ from IP₃-dependent intracellular stores and an increase in both the number of LDCVs and N-type VGCCs at the plasma membrane, thus priming the exocytosis machinery for subsequent activity-dependent release. Although some members of the SNARE family are detectable by immunocytochemistry, there appears to be a lack of VAMP, SNAP-25 and synaptotagmin-1 in the somata-dendrites, with their function presumably being replaced by other SNARE proteins. TG, thapsigargin; CPA, cyclopiazonic acid. (B). Features of somatodendritic dopamine release. Dopamine is synthesized in the intracellular compartment from tyrosine via TH. This process generates L-DOPA which is converted to dopamine by aromatic amino acid decarboxylase (AADC). Synthesized dopamine is stored in tubulovesicular structures that are part of the ER; these structures are the primary site of VMAT2, the vesicular monoamine transporter expressed in dopamine soma and proximal dendrites. Dopamine dendrites contain few vesicles, but those present appear to bud from tubulovesicles. Somatodendritic dopamine release is action potential dependent. Release also requires Ca²⁺ entry via VGCCs, but is amplified by both ryanodine receptors RyRs and metabotropic glutamate receptor (mGluR)-dependent activation of IP₃Rs that release Ca²⁺ from intracellular ER stores. Immunohistochemical evidence suggests that a novel constellation of SNARE proteins may be involved in the release, including SNAP-25, VAMP2, and syntaxin3b. Release from dendrites has also been suggested to involve reversal of the dopamine transporter (DAT). Released dopamine is taken up and recycled via the DAT.