Receptors

Glutamate receptors constitute one of the most structurally diverse and functionally versatile families of signaling proteins in the animal kingdom, mediating the primary excitatory neurotransmission in the vertebrate central nervous system while also fulfilling ancestral roles in metabolic coordination, osmotic regulation, and intercellular communication in organisms lacking centralized nervous systems. This review integrates perspectives from structural biology, evolutionary neuroscience, and systems physiology to provide an updated synthesis of glutamate receptor biology across the tree of life. We examine the molecular architecture and functional properties of ionotropic glutamate receptors AMPA (GluA), NMDA (GluN), and kainate (GluK) and metabotropic glutamate receptors (mGlu1–8), highlighting how subunit composition, RNA editing, alternative splicing, post-translational modifications, and auxiliary protein interactions expand receptor functional diversity beyond what primary gene expression alone can account for. Comparative analyses across vertebrate and non-vertebrate model systems, including Drosophila melanogaster, Caenorhabditis elegans, echinoderms, and cnidarians, reveal deeply conserved ligand-binding and gating mechanisms alongside lineage-specific adaptations that reflect distinct ecological and circuit-level demands. At the systems level, glutamate receptors govern information encoding, oscillatory synchronization, memory consolidation, and homeostatic network stability through coordinated ionotropic and metabotropic signaling. Their dysregulation underlies a broad spectrum of neurological and psychiatric disorders, including excitotoxicity, Alzheimer’s disease, schizophrenia, epilepsy, and major depressive disorder. Recent advances in cryo-electron microscopy, allosteric pharmacology, and gene-editing technologies offer new avenues for subtype-selective therapeutic intervention. Together, these findings underscore glutamate receptors as dynamic molecular platforms that couple synaptic biophysics to emergent neural computation and represent critical targets for next-generation neurotherapeutics.

Background/Objectives: The hippocampus exhibits pronounced functional and physiological heterogeneity along its dorsoventral axis. Sharp wave–ripple (SWR) complexes are highly organized hippocampal network events that depend on coordinated excitation and inhibition and contribute to memory processing. This study investigated whether modulation of the cannabinoid system differentially affects SWRs and associated neuronal activity in the dorsal and ventral hippocampus. Methods: Extracellular field potentials and multiunit activity (MUA) were recorded from the CA1 stratum pyramidale of acute dorsal and ventral rat hippocampal slices. Spontaneous SWRs were analyzed under control conditions and following application of the cannabinoid type 1 (CB1) receptor agonists ACEA and WIN55,212-2, cannabidiol (CBD), and the G-protein-gated inwardly rectifying potassium channel blocker tertiapin-Q. CB1 receptor expression was assessed in dorsal and ventral CA3 using Western blot analysis. Results: Baseline recordings revealed pronounced dorsoventral differences in SWR dynamics. Ventral slices exhibited shorter inter-event intervals, larger sharp-wave amplitudes, higher ripple frequency and power, and greater SWR-associated neuronal activity than dorsal slices. Under the present experimental and analytical conditions, ACEA, WIN55,212-2, and CBD did not produce statistically significant changes in any of the examined SWR or MUA parameters. Tertiapin-Q selectively increased ripple power but did not reveal cannabinoid sensitivity when followed by WIN55,212-2 application. CB1 receptor expression was comparable between dorsal and ventral CA3. Conclusions: Despite marked intrinsic dorsoventral differences in SWR dynamics, acute cannabinoid-system modulation produced no statistically detectable changes in most SWR and MUA parameters examined. These findings indicate that the intrinsic dorsoventral organization of hippocampal SWR activity is robust and remains preserved during acute cannabinoid-system modulation under the present experimental conditions.

GABA (γ-aminobutyric acid) is the most abundant inhibitory neurotransmitter in the central nervous system of insects. GABAergic signal transduction is involved in the control and modulation of various vital functions such as salivation, locomotion, vision and olfaction, circadian timekeeping and sleep, arousal as well as learning and memory. GABA exerts its effects by binding to specific receptors, which are divided into GABA_A and GABA_B receptors. GABA_A receptors are ligand-gated Cl⁻ channels and molecular targets for a variety of small-molecule insecticides (polychlorocycloalkanes such as dieldrin, phenylpyrazoles such as fipronil, isoxazolines, and meta-diamides) that are widely used in agriculture. GABA_B receptors are seven-transmembrane G-protein-coupled receptors. GABA_B receptors function as obligate heteromers consisting of the two subunits, GABA_B-R1 and GABA_B-R2, whereby GABA_B-R1 binds the ligand and GABA_B-R2 is coupled to the G protein. Usually, adenylyl cyclase activity is inhibited via the G_αi subunits of heterotrimeric G proteins; this leads to a reduction in the intracellular cAMP level. This review summarizes the current knowledge on the molecular and pharmacological properties of insect GABA receptors. Finally, two established model organisms for studying the effects of GABA in insects are presented as examples. The American cockroach (Periplaneta americana) has a long tradition as an object to study GABAergic circuits in the olfactory pathway and the role of GABA in the control of salivary secretion. The fruit fly (Drosophila melanogaster) has proven to be an unsurpassed model system to study the effects of GABA and specific GABA receptors on a variety of physiological functions and behavioral processes. In particular, D. melanogaster is used as a disease model for several human diseases in which GABAergic signaling is involved.