Since forskolin is known to act directly at
Since forskolin is known to act directly at the catalytic site of adenylate cyclases near the ATP binding (Tesmer et al., 1997), the synergistic and/or permissive effect of gonadotropins on FSK activity must occur at the level of AC itself or very near, at the level of one of its direct partner. The precise molecular mechanisms of synergy and sensitization by non-human and human LHs and CGs respectively, are currently under study in our laboratory.
Synergy with FSK in adenylate cyclase stimulation has been observed with all LHs and CGs. Since FSK alone does not stimulate cyclic AMP accumulation in MLTC cells, it is possible that these S63845 essentially express type 9 AC that has been described as insensitive to FSK. If type 9 AC is indeed involved, this would indicate that it can become activable by FSK when preactivated by the LHR pathway; likely by a low concentration of GTP-bound Gαs protein. The activated Gαs protein is known to interact with the AC intracellular N-terminal loop whereas FSK binds to the catalytic site between the two AC intracellular loops. Therefore, Gαs protein binding might induce a conformational change in the AC catalytic site allowing FSK binding and action.
Sensitization of AC to FSK has been only observed with human LHs and CGs that are irreversibly bound to the cells probably because of LHR internalization. Microaggregation of occupied LHR with Gs protein and AC together with AKAP and PKA (Sposini and Hanyaloglu, 2017) during this process might stabilize AC in a FSK-sensitive state. It will be particularly interesting to study the relationships between hormone structures in the two groups and these suspected intracellular mechanisms.
A number of irritants such as dental caries, bacterial toxins, operative restoration materials, and traumatic injuries may induce pulpal inflammation and even necrosis of the human dental pulp. Various prostanoids such as prostaglandin E2 (PGE), prostaglandin F2 (PGF2), and prostaglandin I2 (PGI) play crucial roles in these processes to regulate pulpal inflammation and repair , , . PGE and PGI may be involved in the pathogenesis of pulpal inflammation via an increase of vascular permeability in experimental pulpal inflammation of rats and vascular blood flow and tissue edema , . Interleukin (IL)-1α and IL-1β, 2 proinflammatory cytokines, also induce cyclooxygenase-2 expression and prostanoids’ (PGE and PGF) production of dental pulp cells , . On the other hand, tumor necrosis factor α and IL-1α stimulated metalloproteinase-1 (MMP-1), IL-6, and tissue inhibitor metalloproteinase-1 (TIMP-1) expression of pulp cells. PGE alone may also stimulate TIMP-1 expression and suppress intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecules-1 (VCAM-1) expression and secretion in dental pulp cells , , suggesting the anti-inflammatory/tissue repair property of PGE. PGE exerts its effects via the activation of 4 prostaglandin EP receptors (eg, EP1, EP2, EP3, and EP4, which linked to various downstream signal transduction pathways such as adenylate cyclase/cyclic adenosine monophosphate [cAMP]/protein kinase A [PKA] and phospholipase C (PLC)/IP3/calcium mobilization) , , . Recently, pulp cells have been shown to mainly express the EP2 receptor, less amounts of the EP3 and EP1 receptor, and a little amount of the EP4 receptor . To know the signal transduction pathways responsible for PGE-induced pulpal changes is critical for the development of agents against pulpal inflammation. However, the signaling pathways of PGE in dental pulp cells await further clarification. Activation of the EP2 receptor by PGE or other agonists may activate adenylate cyclase in different kinds of cells , , . Adenylate cyclase is a membrane-bound enzyme responsible for cAMP generation and is modulated in various conditions such as psoriatic hyperproliferative epidermis and relaxation of airway smooth muscle , . Recently, cAMP/PKA/cAMP-responsive element-binding protein (CREB) signaling has been shown to mediate osteogenesis of dental pulp stem cells via inducing bone morphogenetic protein-2 (BMP-2), bone sialoprotein, osteocalcin, and type XXIV collagen . Extracellular phosphate is also shown to stimulate BMP-2 expression of dental pulp cells via cAMP/PKA/CREB signaling . On the contrary, activator of G-protein signaling 3 inhibits the TNF-α–induced osteogenic differentiation of dental pulp stem cells via the cAMP/PKA pathway . PGF2α stimulates the mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated kinase (ERK)-CREB/ATF-1 signaling pathway and IL-8 production but suppresses the alkaline phosphatase activity of dental pulp cells. SQ22536, an inhibitor of adenylate cyclase, enhanced the PGF2α-induced IL-8 production , . Whether PGE activates adenylate cyclase and stimulates cAMP production in dental pulp is an interesting issue that should be addressed further.