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Crosstalk between somatostatin receptor subtypes and cannabinoid receptor 1 in excitotoxicity

University of British Columbia

Both somatostatin (SST) and cannabinoid receptor 1 (CB1R) are critical components modulating neurotransmission in the central nervous system (CNS), with sharing functional properties in various neurological activities. To explore their potential crosstalk, first we investigated the expression of SST and CB1R in rat brain hypothalamus and hippocampus. The distributional patterns and colocalization of CB1R and SST were selective and region specific. Neuronal population expressing either SST or CB1R alone, as well as colocalization were seen in various intensities in different regions, suggesting a possible interaction. SST exerts its biological effects via binding to somatostatin receptors (SSTRs). Both SSTRs and CB1R belong to G-protein coupled receptor family that are known to function as oligomers. Accordingly, we investigated the colocalization of CB1R and SSTR5 in rat brain and HEK-293 cells cotransfected with hCB1R and hSSTR5. Our results showed that CB1R and SSTR5 colocalized in rat brain regions. In cotransfected HEK-293 cells, SSTR5 and CB1R existed in a constitutive heteromeric complex under basal condition. Agonist treatments lead to the disruption of CB1R/SSTR5 heterodimer, along with preferential formation of SSTR5 homodimer and dissociation of CB1R homodimer. cAMP and ERK1/2 signaling was modulated in a SSTR5-dominant manner in co-transfected cells. To explore pathological significance of such interaction, we further expanded our study in HD transgenic mice and Huntingtin (Htt) knock-in striatal neuronal cells. We observed significant loss of neuronal subpopulation displaying colocalization between SSTRs and CB1R with selective sparing of SSTR positive neurons in cortex and hippocampus but not in striatum of 11-week-old R6/2 mice, in comparison to wild-type and 7-week-old R6/2 mice. Using mHtt knock-in (STHdhQ¹¹¹/¹¹¹) and wild-type (STHdhQ⁷/⁷) striatal cells, we discovered that STHdhQ¹¹¹/¹¹¹ cells were more vulnerable to QUIN and displayed suppressed cell survival signalings. Receptor-specific agonist protected cells against QUIN-induced toxicity and selectively activated ERK1/2 in both STHdh cells. Co-activation of SSTR subtypes and CB1R resulted in diminished protective effects, delayed ERK1/2 phosphorylation and altered receptor complex composition, with more pronounced effects in STHdhQ¹¹¹/¹¹¹ cells than STHdhQ⁷/⁷ cells. Taken together, our results provide evidence for functional interaction between SSTR and CB1R, emphasizing its therapeutic potentials in excitotoxicity and associated neurological disorders.

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2020-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/64231

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/