Sstr4, short for somatostatin receptor 4, is a receptor expressed in sensory neurons of the peripheral nervous system and various regions of the central nervous system, including the hippocampus, cerebral cortex, striatum, hypothalamus, and thalamus. It is involved in multiple biological processes. Somatostatin, the endogenous ligand, binds to Sstr4, which then couples to diverse second-messenger systems, such as inhibition of adenylate cyclase, activation of arachidonate release, and the mitogen-activated protein kinase cascade [2]. It is implicated in processes like memory formation and has potential significance in pain regulation, mental health, and intestinal pathophysiology.

In the context of pain, venom-inspired Sstr4 agonists like consomatin Fj1 derived from marine cone snail venom have shown analgesic effects in mouse models of postoperative and neuropathic pain, suggesting Sstr4 as a promising target for non-opioid pain therapeutics [1]. In the intestine, genetic ablation of Sstr4 in mice (Sstr4 knockout, Sstr4(-/-)) altered the expression of somatostatin, Sstrs, and neuropeptides in non-inflamed and inflamed conditions, and elevated the expression of substance P and calcitonin gene-related peptide, indicating its role in regulating intestinal SSTR expression and pro-inflammatory neuropeptide expression [3].

In conclusion, Sstr4 is crucial for multiple biological functions. Studies using gene knockout mouse models have revealed its role in pain regulation, intestinal pathophysiology, and potentially mental health disorders. Understanding Sstr4's functions provides new avenues for developing treatments for peripheral pain conditions and may offer insights into mental health-related pathologies.

References:

1. Bjørn-Yoshimoto, Walden E, Ramiro, Iris Bea L, Koch, Thomas Lund, Patwardhan, Amol, Safavi-Hemami, Helena. 2024. Venom-inspired somatostatin receptor 4 (SSTR4) agonists as new drug leads for peripheral pain conditions. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.04.29.591104. https://pubmed.ncbi.nlm.nih.gov/38746149/

2. Bito, H, Mori, M, Sakanaka, C, Nishida, E, Shimizu, T. . Functional coupling of SSTR4, a major hippocampal somatostatin receptor, to adenylate cyclase inhibition, arachidonate release and activation of the mitogen-activated protein kinase cascade. In The Journal of biological chemistry, 269, 12722-30. doi:. https://pubmed.ncbi.nlm.nih.gov/8175684/

3. Van Op den Bosch, Joeri, Torfs, Pascal, De Winter, Benedicte Y, Van Nassauw, Luc, Timmermans, Jean-Pierre. 2009. Effect of genetic SSTR4 ablation on inflammatory peptide and receptor expression in the non-inflamed and inflamed murine intestine. In Journal of cellular and molecular medicine, 13, 3283-95. doi:10.1111/j.1582-4934.2009.00760.x. https://pubmed.ncbi.nlm.nih.gov/19426160/