G protein-coupled receptors (GPCRs) share a common molecular architecture and a common signaling mechanism involving interaction with G proteins (heterotrimeric GTPases) to regulate the synthesis of intracellular second messengers such as cyclic adenosine monophosphate (cAMP), inositol phosphates, diacylglycerol, and calcium ions (Ca2+
). All GPCRs have seven-transmembrane domains (7TM), three extracellular loops (EC1, EC2, EC3), three intracellular loops (IC1, IC2, and IC3), an amino-terminal extracellular domain and an intra-cellular carboxyl terminus (Lefkowitz, 2004
). This topology is predicted from the analysis of hydropathy profiles and from a limited amount of experimental evidence, most importantly from the crystal structure of the visual pigment rhodopsin (Palczewski et al., 2000
), the prototypical class I GPCR for which the activating stimulus is light.
GPCRs are one of the most important classes of signalling proteins as they allow organisms to sense their environment and respond to endogenous hormones and exogenous agents. The superfamily of GPCRs can be divided into six primary classes (denoted below). All of the receptors in each class have several common characteristics, e.g., 7TM repeats, extracellular N-terminus, an intracellular carboxy terminus, and the ability to functionally couple to heterotrimeric G proteins.
Class Ia receptors share a high degree of sequence similarity and tend to bind to small molecular ligands such as catecholamines, small peptides such as opiates, and also small lipids such as the cannabanoid anandamide. The receptor-activating hormones in this family of receptors bind deep in the heptahelical transmembrane bundle. This family is often referred to as “rhodopsin-like” receptors because they are all typified by the light-sensing rhodopsin receptor.
Class Ib receptors are very similar to class Ia but tend to interact with larger ligands, e.g., cytokines, thrombin, and fMLP-peptide. In contrast to Ia receptors ligands for these receptors interact largely with the superficial areas of the heptahelical bundle, extracellular loops, and the N-terminus.
Class Ic receptors differ significantly from the Ia and Ib families owing to their larger N-terminus, often being more than 200 residues in size. This family of receptors also interacts with larger glycoprotein hormones such as luteinizing hormone and thyroid-stimulating hormone. Similar to the Ib family, the receptor–ligand interaction tends to occur mainly with the N-terminus, superficial regions of the helical bundle, and the extra-cellular loops.
Although these receptors share the heptahelical transmembrane structure with the class I receptors, the amino acid sequences of class II and class I receptors are dissimilar. These receptors interact with large, glycoprotein hormones such as secretin, glucagons, and parathyroid hormone via their extremely large (up to 400 residues) extracellular N-terminus. In contrast to the Ic class, the N-terminus appears to be the primary area of receptor–ligand interaction. We discuss the molecular mechanism of the functioning of these receptors and their implications in neuronal physiology and therapeutic neuroprotection in this review.
Similar to class II, these receptors also possess extremely large N-termini that interact with the activating hormone. However in contrast to class II, the ligands are all relatively small in mass, e.g., glutamate, Ca2+, and γ-aminobutyric acid. This GPCR family shares a global structural analogy with classes I and II, but shares very little amino acid sequence identity.
As with classes II and III, this family shares little sequence identity with class I but does share the classical GPCR properties described in the opening paragraph. These vomeronasal (VN) receptors interact with putative pheromone molecules.
These receptors consist of the “frizzled” and “smoothened” receptors involved in embryonic development and in particular in cell polarity and segmentation.
This class consists only of the Dictyostelium discoideum cAMP receptors. These have only been found in D. discoideum and are involved in chemo-taxis of this slime mold.
General Receptor Function
GPCRs have evolved to interact with a chemically diverse array of native ligands, e.g., endogenous compounds like amines, peptides, pheromones, and Wnt proteins (i.e., secreted proteins activating frizzled receptors); endogenous cell surface adhesion molecules; photons and even exogenous compounds like odorants. This review will concentrate on a particular subset of these tremendously important trans-membrane proteins, i.e., the class II family of GPCRs. Class II, often referred to as the secretin-receptor family of GPCRs, is a small but structurally and functionally diverse group of proteins that includes receptors for large polypeptide hormones (Laburthe et al., 1996
). Class II GPCRs have been found in all animal species investigated, including mammals, Caenorhabditis elegans,
and Drosophila melanogaster
, but not in plants, fungi, or prokaryotes. In this article, the structures and functions of class II GPCRs will be described as well as an in-depth review of the roles of these signaling molecules in neuronal degeneration and survival mechanisms. Ligands acting in these systems may, in the near future, prove to be useful therapeutics for neurodegenerative disorders.
The combined use of site-directed mutagenesis and molecular-modeling approaches have provided detailed insights into the molecular mechanisms of ligand binding, receptor activation, G protein-coupling, and regulation of GPCRs. The vast majority of class I, II, III, and VN receptors are able to transduce signals into cells through heterotrimeric G protein-coupling. However, G protein-independent signaling mechanisms have also been reported for many GPCRs. Site-directed mutagenesis and molecular dynamics simulations have revealed that the inactive state conformations are stabilized by specific interhelical and intrahelical salt bridge interactions and hydrophobic-type interactions. Constitutively activating mutations of receptors or agonist binding disrupts such constraining interactions leading to receptor conformations that associate with and activate G proteins.