Synapse最新文献

Several proteins contain signaling domains that can regulate the cell membrane dynamics as well as the underlying cytoskeleton. Among these, Bin-Amphiphysin-Rvs (BAR) domain-containing proteins, with their membrane deforming properties, have emerged as the key players in regulating neuronal morphology and inducing neuronal signaling that can modulate synaptic architecture. While the biochemical and structural basis of membrane deformation by the BAR-domain proteins has been extensively studied, the in vivo contexts in which these proteins function remain to be elucidated. Despite the discovery of BAR-domain proteins over 25 years ago, most of the studies have primarily focused on understanding the structural and biochemical properties and cell biological processes regulated by these proteins. Understanding the functional requirements of these proteins at the level of multicellular organisms and the way these proteins regulate biological processes remains a topic of intensive study. In this review, we discuss the functional roles of BAR-domain proteins in the context of membrane dynamics and cellular signaling. We highlight recent developments describing the functional role of these proteins in neuronal morphogenesis, synaptic function, and disease.

Dopamine transporters (DAT) are transmembrane proteins that translocate dopamine from the extracellular space into presynaptic neurons. We aimed to investigate the predictive power of DAT mRNA for DAT protein expression, measured using positron emission tomography (PET). We performed ¹⁸ F-FP-CIT PET scans in 35 healthy individuals. Binding potentials (BP_ND ) from the ventral striatum, caudate nucleus, putamen, and middle frontal, orbitofrontal, cingulate, parietal, and temporal cortices were measured. DAT gene expression data were obtained from the freely available Allen Human Brain Atlas derived from six healthy donors. The auto-correlation of PET-derived BP_ND s for DAT was intermediate (mean ρ²  = .66) with ρ² ranging from .0811 to 1. However, the auto-correlation of mRNA expression was weak across the probes with a mean ρ² of .09-.23. Cross-correlations between PET-derived BP_ND s and mRNA expression were weak with a mean ρ² ranging from 0 to .22 across the probes. In conclusion, we observed weak associations between DAT mRNA expression and DAT availability in human brains. Therefore, DAT mRNA mapping may have only limited predictive power for DAT availability in humans. However, the difference in distribution of DAT mRNA and DAT protein may influence this limitation.

Acid-sensing ion channels (ASICs) participate in synaptic transmission due to the acidic content of synaptic vesicles, but their contribution to postsynaptic currents is small. This has stimulated attempts to find endogenous ASIC potentiators that could enhance ASIC-mediated currents to physiologically relevant values. Here we demonstrate that glutamate, which serves as a neurotransmitter, potentiates recombinant ASIC1a in the submillimolar concentration range. The effect of glutamate is especially interesting as ASIC's presence has been shown in glutamatergic synapses. At pH=6.5 glutamate had maximum potentiation of 87% with an EC₅₀ value of 0.65 mM. The mechanism of potentiation is due to a shift of pH-dependent activation to less acidic values, with 0.5 mM glutamate increasing pH₅₀ from 6.04 to 6.43. Due to this mechanism, ASIC1a in glutamatergic synapses might be intrinsically potentiated. Furthermore, this effect could compensate for the inhibition of ionotropic glutamate receptors by extracellular acidification during synaptic transmission.

The retromer complex is an evolutionarily conserved protein complex involved in the endosomal recycling of various cargo proteins. It is ubiquitously expressed in all tissue and is found in both invertebrate as well as mammalian nervous systems, where it recycles various synaptic membrane proteins including the dopamine transporter and dopamine D1 receptor, two proteins implicated in dopamine homeostasis and neurotransmission. The involvement of the retromer complex in dopamine neurobiology is further underscored by its links to Parkinson's disease, a neurodegenerative disorder of the dopamine system. In this article, the existing literature linking the retromer complex to synaptic function and dopamine homeostasis is reviewed. Additional possible links are highlighted by exploring the retromer and other Parkinson's disease-associated proteins and possible relationships to synaptic function and dopamine transmission.