Somatostatin, a Presynaptic Modulator of Glutamatergic Signal in the Central Nervous System

Abstract

Somatostatin is widely diffused in the central nervous system, where it participates to control the efficiency of synaptic transmission. This peptide mainly colocalizes with GABA, in inhibitory, GABA-containing interneurons from which it is actively released in a Ca²⁺ dependent manner upon application of depolarizing stimuli. Once released in the synaptic cleft, somatostatin acts locally, or it diffuses in the extracellular space through "volume diffusion", a mechanism(s) of distribution which mainly operates in the cerebrospinal fluid and that assures the progression of neuronal signalling from signal-secreting sender structures towards receptor-expressing targeted neurons located extrasynaptically, in a non-synaptic, inter-neuronal form of communication. Somatostatin controls the efficiency of central glutamate transmission by either modulating presynaptically the glutamate exocytosis or by metamodulating the activity of glutamate receptors colocalized and functionally coupled with somatostatin receptors in selected subpopulations of nerve terminals. Deciphering the role of somatostatin in the mechanisms of "volume diffusion" and in the "receptor-receptor interaction" unveils new perspectives in the central role of this fine tuner of synaptic strength, paving the road to new therapeutic approaches for the cure of central disorders.

Keywords: NMDA receptors; glutamate; metamodulation; noradrenaline; somatostatin; sst2 receptors; sst5 receptors; volume diffusion.

Figure 1

Schematic representation of the intraterminal enzymatic pathways coupled to sst receptors in isolated nerve endings. (left) Somatostatin-14/28 binds sst receptors negatively coupled to adenylyl cyclase (AC) and reduces the endogenous production of cyclic adenosyl monophosphate (cAMP) and the protein kinase A (PKA)-mediated phosphorylative pathways. (right) Somatostatin-14/28 also interacts with sst receptors positively associated to phospholipase C (PLC) then favouring its translocation to the synaptic membranes where the enzyme hydrolyses the phosphoinositides producing inositol trisphosphate (IP₃) and diacylglycerol (DAG), which in turn activate protein kinase C (PKC) and cytosolic tyrosine kinases (src).

Figure 2

Somatostatin localizes in inter-neuronal networks (green neurons) and it is preferentially released, upon application of a depolarizing stimulus, perisynaptically, far from the synaptic active zone. Here, somatostatin can activate auto- and heteroreceptors located extrasynaptically, close to the synaptic active zone, that are referred to as perisynaptic receptors. Somatostatin can also diffuse in the extracellular space, throughout the mechanism of the “volume diffusion” (light green clouds), to activate distant sst receptors located on brain targets far from the site of release.

Figure 3

Depolarization with high-KCl-containing medium favours the opening of VOOCs and the influx of Ca²⁺ ions that triggers glutamate exocytosis either directly through both AC/cAMP/PKA-independent and AC/cAMP/PKA-dependent pathways. Presynaptic release-regulating sst2 heteroreceptors hamper the AC/cAMP/PKA-dependent pathway, then reducing glutamate exocytosis. The sst2-mediated inhibitory effect in turn reverberates on the functions of both metabotropic (mGlu) and ionotropic (NMDA and AMPA) glutamate receptors located postsynaptically, influencing the strength of the connection at glutamatergic synapses.

Figure 4

sst5 receptors activate and upregulate the colocalized and functionally coupled NMDA receptors in hippocampal isolated nerve terminals. A CaMKII-mediated pathway accounts for the sst5 receptor-mediated activation of NMDA receptors in the presence of physiological Mg²⁺ while a concomitant PLC/PKC/Src-mediated enzymatic pathway involving the proline-rich tyrosine kinase 2 (Pyk2) best accounts for the up-regulation of the NMDA receptor-mediated releasing activity.