Extrasynaptic release of GABA and dopamine by retinal dopaminergic neurons
Professor Elio Raviola, Harvard Medical School, USA
In the mouse retina, dopaminergic amacrine (DA) cells synthesize both dopamine and GABA. Both transmitters are released extrasynaptically and act on neighbouring and distant retinal neurons by volume transmission.
In simultaneous recordings of dopamine and GABA release from isolated, perikarya of DA cells, a proportion of the events of dopamine and GABA exocytosis were simultaneous, suggesting co-release.
In addition, DA cells establish GABAergic synapses onto AII amacrines, the neurons that transfer rod bipolar signals to cone bipolars. GABAA but not dopamine receptors are clustered in the postsynaptic membrane. Therefore, dopamine, irrespective of its site of release –synaptic or extrasynaptic– exclusively acts by volume transmission.
Dopamine is released upon illumination and sets the gain of retinal neurons for vision in bright light. The GABA released at DA cells’ synapses probably prevents signals from the saturated rods from entering the cone pathway when the dark-adapted retina is exposed to bright illumination.
The GABA released extrasynaptically by DA and other amacrine cells, probably sets a “GABAergic tone” in the inner plexiform layer and thus counteracts the effects of a spillover of glutamate released at the bipolar cell synapses of adjacent OFF- and ON-strata, thus preserving segregation of signals between ON- and OFF- pathways.
Somatodendritic Dopamine Release
Professor Margaret Rice, New York University, USA
Dopamine (DA) is a key transmitter in motor and emotive pathways of the brain; dysfunction of DA systems has been implicated in disorders that include Parkinson's disease, addiction, and schizophrenia. Located in the midbrain, DAergic neurons of in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) send axon projections via the medial forebrain bundle that provide the sole source of DA to forebrain structures. The DAergic neurons of the SNc project to the dorsal striatum (caudate putamen) and those of the VTA axons project to ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to exhibiting classical vesicular release of DA from their axon terminals, a special feature of these midbrain neurons is that they release DA from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 autoreceptors on DAergic neurons that inhibit the firing of these cells via G-protein-coupled inwardly rectifying K+ channels; this local auto-inhibition helps determine the pattern of DA signaling at distant axonal release sites. Somatodendritic DA release also acts via volume transmission to modulate local transmitter release and neuronal activity in midbrain. Somatodendritic release is therefore a pivotal intrinsic feature of DAergic neurons that must be well defined to understand their physiology and pathophysiology. Recent studies have provided mechanistic insight into the novel Ca2+ dependence of somatodendritic DA release and the potential role of exocytotic proteins in the release process to be discussed in this lecture.
Serotonin somatic release in mammals
Professor Sudipta Maiti, Tata Institute of Fundamental Research, India
Exocytosis from chromaffin cells: Hydrostatic pressure slows vesicle fusion
Professor Walter Stühmer, Max Planck Institute for Experimental Medicine, Germany
Changes in reaction kinetics and equilibrium by hydrostatic pressure are a standard thermodynamic parameter for studying chemical reactions. Here kinetic changes in secretion from chromaffin cells, measured as capacitance changes using the patch clamp technique at pressures of up to 20 MPa (200 Atm), are presented. It is known that these high pressures drastically slow down, in general, physiological functions and increase the effect of general anaesthetics. High hydrostatic pressure only slightly decreases the kinetics of ion channel gating, in particular of voltage-gated Ca2+ channels, albeit it drastically slows down synaptic transmission. This reduction in kinetics by pressure is linked to reactions directly linked to exocytosis of large dense core vesicles in chromaffin cells. Fusion kinetic is slowed down because intermediate steps during the fusion process have a higher equivalent volume (activation volume). The results obtained indicate a similar activation volume of 390±57 Å3 for large dense core vesicle fusion in chromaffin cells and for the degranulation of mast cells. This information will be useful in finding possible protein conformational changes during the reactions involved in vesicle fusion.