Somatostatin and cannabinoid receptors crosstalk in protection of huntingtin knock-in striatal neuronal cells in response to quinolinic acid

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 (STHdhQ111/111) and wild type (STHdhQ7/7) 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, STHdhQ111/111 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. •SSTR2/5 and CB1R are primarily expressed and colocalized intracellularly.•Activation of SSTR2, 5 and CB1R protected STHdh cells from QUIN-induced toxicity.•The protective effect of receptor activation is via ERK1/2.•Combined agonist treatment diminished the protective effect of single treatment.•Composition of receptor complex was altered upon ligand treatment.