Biological and Pharmacological Aspects of the NK1-Receptor

Figure 3

Some of the proposed signaling pathways activated by NK-R. (1) Gαs activation of AC catalyzes ATP to cyclic AMP (cAMP), which in turn binds to the regulatory subunits of the cAMP-dependent PKA. Usually PKA phosphorylates the CREB transcription factor. CREB binds to the cAMP response element (CRE) of a target gene and negatively affects the activation of NF-кB [49]. (2) Inhibition of the AC is performed by Pertussis toxin sensitive Gi protein [48]. Furthermore, Gi and βγ subunits enhance Erk1/2 activation after EGFR-mediated transactivation by Src protein [150]. (3) The SP binding to its receptor triggers a GTP-for-GDP exchange on Gα subunits, thus dissociating Gαq from Gβγ and subsequently activating downstream effectors such as PLC. This enzyme catalyzes the conversion of PIP2 in the second messenger IP3 and DAG, stimulating calcium mobilization and PKC activation, respectively [151]. Via nonreceptor protein kinases such as Src or Pyk2, PKC may activate the MAPK pathway but may also activate the Raf protein directly [77]. Another parallel mechanism that regulates MAPK may be developed during NK-1R internalization and its protein recruitment by β-arrestins [22, 78]. Although the mechanism is unknown, the Erk1/2 protein is also involved in NF-кB activation [84]. This Gαq subunit also mediates IL-6 production by activation of p38 MAPK [152]. (4) The Gα12/13 subunit is responsible for the activation of Rho/Rock which directly regulates the phosphorylation of the myosin light chain (MLC) [52]. Phosphorylation of this protein is associated with cytoskeletal reorganization and cell migration. The βγ dimer activates proteins such as Src, PI3K, and PLC [85]. This figure was made using Servier Medical Art collection (http://creativecommons.org/licenses/by/3.0).