Serotonin Receptors

Ionotropic (5-HT₃)

Metabotropic GPCRs (5-HT₁ → 5-HT₇)

7 transmembrane helices

intracellular loops

regulatory interactions

Ionotropic Serotonin Receptor (5-HT₃)

Pentameric structure

5-HT3A (can form homopentamers) ± 5-HT3B, C, D, E

Extracellular N-terminal domain

Four transmembrane helices per subunit (M1–M4)

M2 helix → central ion channel pore

Intracellular loop (between M3–M4)

Conducts Na⁺, K⁺, Ca²⁺

Metabotropic Serotonin Receptors (GPCRs)

Extracellular N-terminus

receptor folding

ligand recognition

Transmembrane Domains (TM1–TM7)

Seven alpha-helices

Extracellular Loops (ECL1, ECL2, ECL3)

Intracellular Loops (ICL1, ICL2, ICL3)

Cytoplasmic C-terminus

regulatory proteins

receptor desensitization

Ligand-binding pocket

Histamine Receptors

Imidazole ring

Ethanolamine side chain

Asp³·³² (TM3)

H₁ binds antihistamines

H₂ binding site

Cimetidine

EL2

EL3

Intracellular loop 3 (ICL3)

H₁ → Gq (activates PLC → Ca²⁺ release)

H₂ → Gs (activates adenylyl cyclase → cAMP)

H₃ → Gi (inhibits neurotransmitter release)

H₄ → Gi (immune cell modulation)

Aspartate Receptors

α-carboxyl

β-carboxyl

Positively charged residues

Venus flytrap domain (VFT)

Ligand-induced domain closure

Ionotropic

AMPA

NMDA-like

Allosteric modulation sites

Pure excitatory neurotransmitter

Voltage-dependent gating

Co-agonists

Glutathione Receptors

Tripeptide antioxidant (γ-glutamyl-cysteinyl-glycine)

Tripeptide glutathione

Oxidized glutathione (GSSG)

GSH/GSSG ratio

Redox signaling

Detoxification

γ-glutamyl transpeptidase (GGT)

Glutathione transporters

ATP-binding cassette

MRP/ABCC family

Norepinephrine Receptors

7-transmembrane GPCR structure

Presynaptic autoreceptor domains

β → Gs → stimulates adenylyl cyclase → ↑ cAMP

α2 → Gi → inhibits adenylyl cyclase → ↓ cAMP

α1 → Gq → phospholipase C activation → IP₃/DAG → intracellular calcium rise

Acetylcholine Receptors

nicotinic

muscarinic

Ionotropic (nAChR)

Metabotropic (mAChR)

cation-selective pore

Na⁺ influx and K⁺ efflux

Subunit (α, β, γ, δ, ε)

Gi, Gq, Gs

D-Serine Receptors

resting potentials

NR1 subunit

NR2 subunits

glycine-binding modulatory site

ionotropic glutamate receptors

NMDARs

co-agonist of NMDA-type glutamate receptors (NMDARs)

long-term potentiation (LTP)

Adenosine Receptors

purine nucleoside

A1

A2A

A2B

A3

metabolic signal

tonic activation

cellular energy state

Heterodimerization

functional antagonism

modulators of neural tone

Neuroprotective

Anti-Excitotoxic

ATP Receptors

energy nucleotide

Trimeric

ionotropic

metabotropic GPCR

Desensitization Patterns

Pentameric nicotinic receptors

Tetrameric AMPA/NMDA receptors

P2X7

P2X Receptors

P2Y Receptors

purinergic receptor family

Microglia

Macrophages

Neutrophils

Damage-associated molecular pattern (DAMP) sensors

IL-1β release

Inflammasome activation

Endorphins (β-endorphin)

31–amino acid peptide

β-arrestin

ACTH

α-MSH

μ-opioid receptors

proteolytic processing

POMC

synaptic suppression

analgesia

Periaqueductal gray

Spinal cord dorsal horn

Limbic system

Endogenous Analgesic System

Nitric Oxide

Ferrous state (Fe²⁺)

NO oxidation state

NO dissociation

GTP → cGMP

Prosthetic heme (Fe²⁺-protoporphyrin IX) group

Heme-Binding Domain

β-subunit H-NOX domain

Redox Sensitivity

Activation Kinetics

Soluble Cytoplasmic Localization

β subunit

α subunit

Heterodimeric Structure (α + β subunits)

Soluble guanylate cyclase (sGC)

NO → sGC → directly synthesizes cGMP

Neuropeptide Y (NPY)

C-terminal tyrosine–amide (Tyr36–NH₂)

DRY motif

serine/threonine clusters

TM3

TM5

TM6

TM7

intact N-terminal region

C-terminal fragments

PYY fragments

NPY(13–36)

PYY(3–36)

PP-fold C-terminal helix

36–amino acid peptide

PP-fold structure

large amphipathic helix–turn–helix peptide

ECL2

Intracellular Loop 3 (ICL3)

ICL3 amino acid motifs

Subtype-specific GRK phosphorylation

GRK phosphorylation profile

C-Terminal Tail Phosphorylation Pattern

distinct C-terminal tail sequence

TM6/TM7 Microarchitecture

binding pocket geometry

7TM bundle

rhodopsin-like

Gi/o proteins

GIRK channels

adenylyl cyclase

β-arrestin recruitment dynamics

High Affinity Nanomolar Binding

nM range affinity

Dimerization

homo- and heterodimers

presynaptic autoreceptor

hypothalamic nuclei

Y1 selectivity

BIBP 3226

Neuropeptide Y receptor Y1

Neuropeptide Y receptor Y2

Neuropeptide Y receptor Y5

Somatostatin

disulfide bond

Phe⁷

Trp⁸

Lys⁹

Thr¹⁰

TM3

TM6

TM7

rigid cyclic core

disulfide-constrained loop

tetrapeptide core

Phe–Trp–Lys–Thr pharmacophore motif

Cyclic Peptide

phosphotyrosine phosphatases

SHP-1

SHP-2

MAPK signaling

cell cycle arrest

Alternative Splice Variants

SSTR2A

SSTR2B

Homo- and Heterodimerization

cross-family dimerization

Antiproliferative Signaling Mechanisms

SSTR1

SSTR2

SSTR1–5

SSTRs

Cholecystokinin (CCK)

Tyr-sulfate

Trp–Met–Asp–Phe–NH₂ (C-terminal amidated tetrapeptide)

non-sulfated CCK

CCK peptide

C-terminal α-helical

sulfated peptide binding

peptide-binding site

sulfotyrosine-recognition pocket

ECL2/TM3

ECL3

TM6/TM7

TM5–TM7 cavity geometry

TM Domain Microarchitecture

differential selectivity

Gi/o

Gq coupling determinants

dual signaling capacity

phospholipase C and Ca²⁺

GRK-mediated phosphorylation

surface signaling

functional localization

CCK₁R

CCK₂R

devazepide