Search Results (5)

Parathyroid Hormone (PTH) plays a crucial role in the maintenance of calcium homeostasis directly acting on bone and kidneys and indirectly on the intestine. However, a large family of PTH-related peptides exists that exerts other physiological effects on different tissues and organs, such as the Central Nervous System (CNS). In humans, PTH-related peptides are Parathyroid Hormone (PTH), PTH-like hormones (PTHrP and PTHLH), and tuberoinfundibular peptide of 39 (TIP39 or PTH2). With different affinities, these ligands can bind parathyroid receptor type 1 (PTH1R) and type 2 (PTH2R), which are part of the type II G-protein-coupled-receptors (GPCRs) family. The PTH/PTHrP/PTH1R system has been found to be expressed in many areas of the brain (hippocampus, amygdala, hypothalamus, caudate nucleus, corpus callosum, subthalamic nucleus, thalamus, substantia nigra, cerebellum), and literature data suggest the system exercises a protective action against neuroinflammation and neurodegeneration, with positive effects on memory and hyperalgesia. TIP39 is a small peptide belonging to the PTH-related family with a high affinity for PTH2R in the CNS. The TIP39/PTH2R system has been proposed to mediate many regulatory and functional roles in the brain and to modulate auditory, nociceptive, and sexual maturation functions. This review aims to summarize the knowledge of PTH-related peptides distribution and functions in the CNS and to highlight the gaps that still need to be filled. Full article

Formyl peptide receptor type 2 (FPR2/ALX) belongs to the formyl peptide receptors (FPRs) family clustered on chromosome 19 and encodes a family of three Class A of G protein-coupled receptors (GPCRs). A short N-terminal region, an NPXXY motif in transmembrane (TM) region 7 and an E/DRY motif that bridges TM3 and TM6 stabilizing inactive receptor conformations characterize this class of receptors. In recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), FPRs play a crucial role in innate immune responses. FPR2/ALX is highly expressed in myeloid cells, as well as in chondrocytes, fibroblasts, endothelial, epithelial and smooth muscle cells. FPR2/ALX mRNA expression was recently reported in the rat brainstem, spinal cord, thalamus/hypothalamus, cerebral neocortex, hippocampus, cerebellum and striatum. The central nervous system (CNS) distribution of FPR2/ALX suggests important functions in nociception. Thus, the present study was carried out to investigate the possible role of FPR2/ALX in nociception in mice. Intrathecal administration of the formyl peptide receptor type 1 (FPR1) agonist fMLF and the FPR2/ALX agonist BML-111 relieved nociception and these effects were reduced by contemporary administration of the FPR2/ALX antagonist WRW⁴. Furthermore, measurement of cytokines and brain-derived neurotrophic factor (BDNF) in the spinal cord of neuropathic mice demonstrated that the antinociceptive effects of BML-111 might depend on the reduction in cytokine release and BDNF in the spinal cord. These results suggest a possible role of FPR2/ALX for pain control in the spinal cord. Full article

The free fatty acid FFA3 receptor (FFA3R) belongs to the superfamily of G-protein-coupled receptors (GPCRs). In the intestine and adipose tissue, it is involved in the regulation of energy metabolism, but its function in the brain is unknown. We aimed, first, to investigate the expression of the receptor in the hippocampus of Alzheimer disease (AD) patients at different stages of the disease and, second, to assess whether genetic inactivation of the Ffar3 gene could affect the phenotypic features of the APP_swe mouse model. The expression of transcripts for FFA receptors in postmortem human hippocampal samples and in the hippocampus of wild-type and transgenic mice was analyzed by RT-qPCR. We generated a double transgenic mouse, FFA3R^−/−/APP_swe, to perform cognition studies and to assess, by immunoblotting Aβ and tau pathologies and the differential expression of synaptic plasticity-related proteins. For the first time, the occurrence of the FFA3R in the human hippocampus and its overexpression, even in the first stages of AD, was demonstrated. Remarkably, FFA3R^−/−/APP_swe mice do not have the characteristic memory impairment of 12-month-old APP_swe mice. Additionally, this newly generated transgenic line does not develop the most important Alzheimer’s disease (AD)-related features, such as amyloid beta (Aβ) brain accumulations and tau hyperphosphorylation. These findings are accompanied by increased levels of the insulin-degrading enzyme (IDE) and lower activity of the tau kinases GSK3β and Cdk5. We conclude that the brain FFA3R is involved in cognitive processes and that its inactivation prevents AD-like cognitive decline and pathological hallmarks. Full article

Endocannabinoid signaling depends upon the CB₁ and CB₂ cannabinoid receptors, their endogenous ligands anandamide and 2-arachidonoylglycerol, and intracellular proteins that mediate responses via the C-terminal and other intracellular receptor domains. The CB₁ receptor regulates and is regulated by associated G proteins predominantly of the Gi/o subtypes, β-arrestins 1 and 2, and the cannabinoid receptor-interacting protein 1a (CRIP1a). Evidence for a physiological role for CRIP1a is emerging as data regarding the cellular localization and function of CRIP1a are generated. Here we summarize the neuronal distribution and role of CRIP1a in endocannabinoid signaling, as well as discuss investigations linking CRIP1a to development, vision and hearing sensory systems, hippocampus and seizure regulation, and psychiatric disorders including schizophrenia. We also examine the genetic and epigenetic association of CRIP1a within a variety of cancer subtypes. This review provides evidence upon which to base future investigations on the function of CRIP1a in health and disease. Full article

Cognition and other higher brain functions are known to be intricately associated with the capacity of neural circuits to undergo structural reorganization. Structural remodelling of neural circuits, or structural plasticity, in the hippocampus plays a major role in learning and memory. Dynamic modifications of neuronal connectivity in the form of dendritic spine morphology alteration, as well as synapse formation and elimination, often result in the strengthening or weakening of specific neural circuits that determine synaptic plasticity. Changes in dendritic complexity and synapse number are mediated by cellular processes that are regulated by extracellular signals such as neurotransmitters and neurotrophic factors. As many neurotransmitters act on G protein-coupled receptors (GPCRs), it has become increasingly apparent that GPCRs can regulate structural plasticity through a myriad of G protein-dependent pathways and non-canonical signals. A thorough understanding of how GPCRs exert their regulatory influence on dendritic spine morphogenesis may provide new insights for treating cognitive impairment and decline in various age-related diseases. In this article, we review the evidence of GPCR-mediated regulation of structural plasticity, with a special emphasis on the involvement of common as well as distinct signalling pathways that are regulated by major neurotransmitters. Full article