Somatostatin receptors in the central nervous system

doi:10.1016/0301-0082(96)00030-5

Progress in Neurobiology

Volume 50, Issue 1, September 1996, Pages 9-37, 39-47

https://doi.org/10.1016/0301-0082(96)00030-5 Get rights and content

Abstract

Somatostatin was first identified chemically in 1973, since when much has been established about its synthesis, storage and release. It has important physiological actions, including a tonic inhibitory effect on growth hormone release from the pituitary. It has other central actions which are not well understood but recent cloning studies have identified at least five different types of cell membrane receptor for somatostatin. The identification of their genes has allowed studies on the distribution of the receptor transcripts in the central nervous system where they show distinct patterns of distribution, although there is evidence to indicate that more than one receptor type can co-exist in a single neuronal cell. Receptor selective radioligands and antibodies are being developed to further probe the exact location of the receptor proteins. This will lead to a better understanding of the functional role of these receptors in the brain and the prospect of determining the role, if any, of somatostatin in CNS disorders and the identification of potentially useful medicines.

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Citation Excerpt :
SST, also known as somatotropin release-inhibiting factor, is a growth hormone inhibitory peptide that suppresses the cell growth. In the CNS, SST serves as a neurotransmitter and neuromodulator and is involved in the regulation of a variety of neurological activities, including cognition, locomotor, sensory and autonomic functions (Schindler et al., 1996; Patel, 1999; Kumar and Grant, 2010). There is growing evidence suggesting that SST plays a critical role in various neurodegenerative diseases including Alzheimer's disease, HD, Parkinson's disease, multiple sclerosis, as well as neuropsychological disorders including major depression and schizophrenia (Aronin et al., 1983; Epelbaum et al., 1983; Sorensen, 1987; Beal et al., 1988; Burgos-Ramos et al., 2008; Tallent and Qiu, 2008; Lin and Sibille, 2013).
In the present study, we describe the status of somatostatin receptor 2 and 5 (SSTR2 and SSTR5) as well as cannabinoid type 1 receptor (CB1R) in Huntingtin (Htt) knock-in striatal neuronal cells. In mutant Htt (mHtt) knock-in (STHdh^Q111/111) and wild type (STHdh^Q7/7) striatal neuronal cells, SSTRs and CB1R exhibit prominent cytoplasmic expression and respond to agonist in a receptor specific manner. In response to quinolinic acid (QUIN)-induced toxicity, STHdh^Q111/111 cells are more vulnerable and display suppressed cell survival signaling pathways. Receptor-specific agonists protect cells from QUIN-induced toxicity and activate ERK1/2 in both STHdh cells. Co-activation of SSTRs and CB1R resulted in loss of protective effects, delayed ERK1/2 phosphorylation and altered receptor complex composition. These results provide firsthand evidence in support of the protective role of SSTRs in STHdh cells and the possible crosstalk between SSTRs and CB1R in the modulation of excitotoxicity in Huntington's disease.
Sustained somatostatin gene expression reverses kindling-induced increases in the number of dividing Type-1 neural stem cells in the hippocampi of behaviorally responsive rats
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Neurogenesis persists throughout life in the hippocampi of all mammals, including humans. In the healthy hippocampus, relatively quiescent Type-1 neural stem cells (NSCs) can give rise to more proliferative Type-2a neural progenitor cells (NPCs), which generate neuronal-committed Type-2b NPCs that mature into Type-3 neuroblasts. Many Type-3 neuroblasts survive and mature into functionally integrated granule neurons over several weeks. In kindling models of epilepsy, neurogenesis is drastically upregulated and many new neurons form aberrant connections that could support epileptogenesis and/or seizures. We have shown that sustained vector-mediated hippocampal somatostatin (SST) expression can both block epileptogenesis and reverse seizure susceptibility in fully kindled rats. Here we test whether adeno-associated virus (AAV) vector-mediated sustained SST expression modulates hippocampal neurogenesis and microglial activation in fully kindled rats. We found significantly more dividing Type-1 NSCs and a corresponding increased number of surviving new neurons in the hippocampi of kindled versus sham-kindled rats. Increased numbers of activated microglia were found in the granule cell layer and hilus of kindled rats at both time points. After intrahippocampal injection with either eGFP or SST-eGFP vector, we found similar numbers of dividing Type-1 NSCs and -2 NPCs and surviving BrdU⁺ neurons and glia in the hippocampi of kindled rats. Upon observed variability in responses to SST-eGFP (2/4 rats exhibited Grade 0 seizures in the test session), we conducted an additional experiment. We found significantly fewer dividing Type-1 NSCs in the hippocampi of SST-eGFP vector-treated responder rats (5/13 rats) relative to SST-eGFP vector-treated non-responders and eGFP vector-treated controls that exhibited high-grade seizures on the test session. The number of activated microglia was upregulated in the GCL and hilus of kindled rats, regardless of vector treatment. These data support the hypothesis that sustained SST expression exerts antiepileptic effects potentially through normalization of neurogenesis and suggests that abnormally high proliferating Type-1 NSC numbers may be a cellular mechanism of epilepsy.
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Like cannabinoids, somatostatin (SST) plays a critical role in many pathological conditions through binding to five different receptor subtypes, namely somatostatin receptor 1–5 (SSTR1–5). SSTR subtypes are well-expressed in the CNS in a region- and receptor-specific manner (Schindler et al., 1996; Patel, 1999; Ramirez et al., 2004; Kumar, 2007). Although the expression of SSTR5 in the CNS is relatively low in comparison to other SSTR subtypes, its pathophysiological significance in neurological disorders has been supported by several studies (Craft et al., 1999; Stroh et al., 1999; Kumar, 2005; Watson et al., 2009).
Endocannabinoids and somatostatin (SST) play critical roles in several pathophysiological conditions via binding to different receptor subtypes. Cannabinoid receptor 1 (CB1R) and somatostatin receptors (SSTRs) are expressed in several brain regions and share overlapping functions. Whether these two prominent members of G-protein-coupled receptor (GPCR) family interact with each other and constitute a functional receptor complex is not known. In the present study, we investigated the colocalization of CB1R and SSTR5 in rat brain, and studied receptor internalization, interaction and signal transduction pathways in HEK-293 cells cotransfected with human cannabinoid receptor 1 (hCB1R) and hSSTR5. Our results showed that CB1R and SSTR5 colocalized in rat brain cortex, striatum, and hippocampus. CB1R was expressed in SSTR5 immunoprecipitate prepared from the brain tissue lysate, indicating their association in a system where these receptors are endogenously expressed. In cotransfected HEK-293 cells, SSTR5 and CB1R existed in a constitutive heteromeric complex under basal condition, which was disrupted upon agonist treatments. Furthermore, concurrent receptor activation led to preferential formation of SSTR5 homodimer and dissociation of CB1R homodimer. We also discovered that second messenger cyclic adenosine monophosphate and downstream signaling pathways were modulated in a SSTR5-dominant and concentration-dependent manner in the presence of receptor-specific agonist. In conclusion, with predominant role of SSTR5, the functional consequences of crosstalk between SSTR5 and CB1R resulting in the regulation of receptor trafficking and signal transduction pathways open new therapeutic avenue in cancer biology and excitotoxicity.
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The majority of the synapses in the central nervous system contain peptides, which regulate important physiological processes (Malavolta and Cabral, 2011). Somatostatin (SST) is a tetradecapeptide, which is widely expressed in the mammalian central and peripheral nervous systems (Carlton et al., 2004; Schindler et al., 1996; Schulz et al., 1998a; Shi et al., 2014). The corresponding high affinity somatostatin receptors are G protein-coupled receptors, which are divided into 5 subtypes (sstr1–5) (Lahlou et al., 2004).
Somatostatin (SST) and the somatostatin receptor type 2 (sstr2) are expressed in the superficial part (Laminae I–III) of the dorsal horn of the spinal cord. Since the neurons in these laminae also receive nociceptive sensation from the periphery, it was hypothesized that both SST and sstr2 could be involved in the modulation of nociceptive transmission. To the best of knowledge, there are no studies on the involvement of SST and sstr2 in hind paw incision model in rats, which mimics postoperative pain in humans. Sprague-Dawley rats were subjected to hind paw incision under isoflurane anaesthesia and the resulting mechanical allodynia and thermal hyperalgesia were evaluated for 5 days. In another set of animals, the spinal cord was isolated at specified time intervals after incision and examined for SST and sstr2 expression using immunohistochemistry and immunoblotting procedures. Finally, nociceptive parameters were again evaluated in incised rats, which had received SST (400 µg/kg i.p. three times per day). Blood glucose level and locomotor activity were determined after SST treatment. Both allodynia and hyperalgesia were highest immediately after incision. Spinal SST expression increased at 2 h. A further increase was noted on day 3. Expression of sstr2 increased initially but decreased at day 1. These changes could be due to exocytosis of SST and internalization of the ligand–receptor complex. SST injection significantly attenuated mechanical allodynia but not thermal hyperalgesia. Significant change in blood glucose level or locomotor activity was absent. SST appears to contribute to postincisional pain. This finding could be of clinical relevance.
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2009, Journal of Chemical Neuroanatomy
Apolipoprotein D (ApoD) is widely distributed in central and peripheral nervous system. ApoD expression has been shown to increase in several neurodegenerative and neuropsychiatric disorders, as well as during regeneration in the nervous system. Like ApoD, in the central nervous system somatostatin (SST) is widely present and functions as neurotransmitter and neuromodulator. The biological effects of SST are mediated via binding to five high-affinity G-protein coupled receptors termed SSTR1–5. Mice lacking ApoD exhibit reduced SST labeling in cortex and hippocampus and increased expression in striatum and amygdala without any noticeable changes in substantia nigra. Changes in SSTRs expressions have been described in several neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's diseases. In the present study, using SSTR1–5 receptor-specific antibodies, we mapped their distribution in wild type ( $w t$ ) and ApoD knockout (ApoD^−/−) mouse brain. SSTR1–5 expression was observed both as membrane and cytoplasmic protein and display regions and receptor specific differences between $w t$ and ApoD^−/− mice brains. In cortex and hippocampus, SSTR subtypes like immunoreactivity are decreased in ApoD^−/− mice brain. Unlike cortex and hippocampus, in the striatum of ApoD^−/− mice, projection neurons showed increased SSTR immunoreactivity, as compared to $w t$ . Higher SSTR subtypes immunoreactivity is seen in substantia nigra pars compacta (SNpc) whereas lower in substantia nigra pars reticulata (SNpr) of ApoD^−/− mice brains as compared to $w t$ . Whereas, amygdala displayed SSTR subtypes changes in different nuclei of ApoD^−/− mice in comparison to $w t$ mice brain. Taken together, our results describe receptor and region specific changes in SST and SSTR subtypes expression in ApoD^−/− mice brain, which may be linked to specific neurological disorders.

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