Adenylyl cyclase signaling mechanisms of relaxin and insulin action: Similarities and differences

Abstract

The adenylyl cyclase signaling mechanism (ACSM) of relaxin H2 action was discovered and deciphered in mammalian muscles. A study of signaling blocks involved in ACSM of relaxin in comparison with that of insulin previously detected showed a close similarity throughout the post-receptor signaling chain of both hormones. The inhibitory action of tyrosine kinase blockers on the hormone AC activating effect indicates that the relaxin receptor involved in ACSM is likely to be of the tyrosine kinase type. However, a recent discovery of a relaxin receptor with serpentine architecture leaves open the question concerning the existence of receptor of the tyrosine kinase type. The structural-functional organization of the ACSM due to the action of relaxin-shown here for the first time-can be presented as the following signaling sequence: relaxin receptor ==>G(i) protein (betagamma-dimer) ==>phosphatidylinositol 3-kinase ==>protein kinase Czeta ==>G(s) protein ==>adenylyl cyclase. According to our hypothesis, the regulatory action of the insulin superfamily peptides on cell processes (proliferation, apoptosis, and metabolism) is mediated via ACSM.

Functional defects in adenylyl cyclase signaling mechanisms of insulin and relaxin in skeletal muscles of rat with streptozotocin type 1 diabetes

“…According to our previous findings, the structuralfunctional organization of ACSM of insulin can be described as the following signaling cascade: receptor-tyrosine kinase → G protein of inhibitory type (G i -protein) (Gβγ-dimer) → phosphatidylinositol 3-kinase → protein kinase Cζ → G protein of stimulatory type (G s protein) → AC ( Figure 1). Relaxin-induced ACSM has a similar signal transduction organization at the post-receptor stages [4,7]. There is, however, one difference concerning the relaxin receptor.…”

“…However, there are data in favor of the existence of tyrosine kinase type relaxin receptors (such that tyrosine kinase blockers posses an inhibitory action on relaxin signaling) [4,5,10,11]. This allowed us to hypothesize the presence of both types of relaxin receptors, possibly scattered in different target tissue.…”

“…This includes firstly molecular defects in the hormonal signaling systems as the key causes of endocrine diseases [1]; and, secondly, the discovery of a novel, adenylyl cyclase signaling mechanism (ACSM) of insulin and relaxin action in rat skeletal muscles [2][3][4][5][6][7].…”

The effect of relaxin on the musculoskeletal system

“…Relaxin helps regulate normal skeletal muscle through two principle signaling pathways: AC and nitric oxide (NO). Relaxin activates the AC signaling pathway in skeletal muscles through the following signal chain: relaxin receptor tyrosine kinase → Gi protein (βγ‐dimer) → phosphatidylinositol 3‐kinase (PI3K) → protein kinase Cz (PKCζ) → heterotrimeric Gs protein → AC → protein kinase A (Kuznetsova et al., ; Shpakov et al., , , b, , ; Pertseva et al., ; Plesneva et al., ). Relaxin also activates the NO pathway in skeletal muscle via relaxin‐mediated activation of receptor tyrosine kinase → Gi protein → PI3K → protein kinase D1 → protein kinase B → NO (Plesneva et al., ).…”

Variations in Functional Activity of the Hormone-Sensitive Adenylate Cyclase System in Tissues of Gastropod Mollusks with Streptozotocin-Induced Diabetes

“…Other reagents were manufactured by Sigma and Reanal. AC activity was measured with [α-32 P]ATP (30 Ci/mol, Amersham) as described elsewhere [12,14]. The membrane fraction was incubated in the reaction mixture at 30 o C for 10 min.…”