The Luteinizing Hormone/Chorionic Gonadotropin Receptor Has Distinct Transmembrane Conductors for cAMP and Inositol Phosphate Signals

Abstract

The luteinizing hormone/chorionic gonadotropin receptor is a member of the seven-transmembrane receptor family. It is coupled, presumably via G s and G q , to two signal pathways involving adenylyl cyclase/cAMP and phospholipase C/inositol phosphate (IP). Little is known about the events prior to G-protein coupling: for example, whether these signals are generated from a single or multiple independent origins and mechanisms, when and where they diverge, and how they are transduced. We report novel observations that the cAMP signal and the IP signal originate and diverge upstream of G-protein coupling. The LH/CG 1 receptor is a member of the seven-transmembrane (TM) receptor family and comprises two distinct functional domains consisting of the extracellular N-terminal half and the membrane-associated C-terminal half. These two domains are encoded by 11 exons (1, 2). Exons 1-10 encode the extracellular N-terminal domain, which alone is responsible for high affinity hormone binding (3)(4)(5). This distinguishes the LH/CG receptor and other glycoprotein hormone receptors from all other seven-TM receptors, which have the high affinity ligand binding sites in the membrane-associated domain (6). Exon 11 of the LH/CG receptor encodes the membrane-associated domain, which is capable of low affinity hormone binding and receptor activation (5, 7). This membrane-associated domain includes seven-TM helices joined together by three exoloops and three cytoloops.The LH/CG receptor is coupled to the adenylyl cyclase and PLC signal pathways, inducing the production of cAMP and inositol phosphates (IPs) as intracellular signal molecules (8). These signal molecules are produced when the receptor couples, presumably through G s and G q (9), to adenylyl cyclase and PLC, respectively (10). However, little is known about the events prior to G-protein coupling (6) (in particular, when more than one signal is involved). As a first step to lead discussion, several simple mechanisms are hypothesized for dual signals as shown in Fig. 1. Hormonal signal generation and transfer can be likened to an electrical circuit. Contact between the hormone and the receptor acts as an on/off signal switch and the receptor conducts the signal to the terminal cytodomain G-protein dock. Signals may be generated and transferred by single switch/single conductor, single switch/dual conductors, or dual switches/dual conductors. We will examine these models in light of the existing evidence.Recent investigations have identified several amino acids of the LH/CG receptor that are important for receptor activation (11)(12)(13)(14)(15)(16)(17)(18)(19). Most of these amino acids are present in cytoplasmic or TM domains. Only a few were found in the extracellular regions of the LH/CG receptor (11,12,(17)(18)(19). The added significance of extracellular amino acids in receptor activation is that they are near or at the hormone binding domain and could be involved in signal generation (6). Although their involvement in cAMP induction has been extensively examined, non...

The Role of Asp578 in Maintaining the Inactive Conformation of the Human Lutropin/Choriogonadotropin Receptor

“…3). This may be due to differences in coupling effi- ciency or to the fact that different receptor conformations are involved in activating the two pathways (25,26 (27,28). In contrast to our data on the LHR, the Asp 633 3 Tyr TSHR mutant did not appear to possess a more strongly activating phenotype than Asp 633 3 Glu or other TSHR mutations, nor did it cause constitutive activation of the inositol phosphate pathway (28).…”

Expression of the Metastasis Suppressor KAI1 in Decidual Cells at the Human Maternal-Fetal Interface

“…1 In pregnancy, the decidua is exposed to vast amounts of human chorionic gonadotropin (hCG) secreted by the syncytiotrophoblast, and signaling through the luteinizing hormone/hCG receptor involves cAMP as a second messenger. 44 All of these ligands are candidates for cAMPdependent induction of decidual KAI1 expression, which we demonstrated in vivo in secretory phase endometrium and in the decidua of pregnancy at least up to the second trimester. We also showed that in cultured decidual cells isolated from term placenta, basal KAI1 expression was present and could further be stimulated by cAMP treatment.…”

The C-terminal Third Intracellular Loop of the Rat AT1A Angiotensin Receptor Plays a Key Role in G Protein Coupling Specificity and Transduction of the Mitogenic Signal

“…Recently, mutations in the third exoplasmic loop of the luteinizing hormone/choriogonadotropin receptor have been shown to abolish preferentially cAMP induction, being more permissive for the IP signaling (45). Moreover, a mutation in the third transmembrane domain of the ␣ 1 -AR produced a constitutive activation of the IP signaling, without affecting the phospholipase A 2 induction (46).…”