VIP-Activated Signal Transduction Pathways

VIP interacts with specific VIP receptors located on the basolateral membranes of lacrimal gland cells. Two types of VIP receptors have been identified, VIPRI and VIPRII, which are also known as VIPACR1 and VIPACR2, and both of them are expressed in the lacrimal gland, with VIPRI being the predominant type.

Adenylate cyclase-coupled signaling pathway

The VIP receptor uses the G protein Gas to activate the effector enzyme adenylyl cyclase (AC), which produces the second-messenger molecule, cyclic adenosine monophosphate (cAMP) (Figure 6). Molecular cloning has identified several isoforms of mammalian AC forming a family of at least 10 enzymes (ACI-X). There are at least three isoforms of AC (ACII, ACIII, and ACIV) present in the lacrimal gland, each having a unique localization.

Although the regulation of AC enzymatic activity is complex and isoform specific, all AC isoforms are activated

Figure 6 Schematic depicting the main signal transduction pathways activated by the VIP to stimulate protein secretion. The activation of lacrimal gland VIP receptors activates two main signaling pathways that enhance protein secretion.

By Gas. Increases in the intracellular levels of cAMP lead to activation of protein kinase A (PKA), a ubiquitous serine and threonine protein kinase. In its inactive state, PKA consists of a complex of two catalytic (C) subunits and two regulatory (R) subunits (Figure 6). Binding of cAMP to the R subunit alleviates an autoinhibitory contact that releases the active C subunit (Figure 6). The active kinase is then free to phosphorylate specific protein substrates to stimulate lacrimal gland protein and fluid secretion.

MAPK-coupled signaling pathway

Recently, it has been shown that addition of VIP, exogenous cAMP, or analogs that increase cAMP levels inhibited both basal as well as cholinergic induced activation of MAPK in the lacrimal gland. One implication of these findings is that it could help explain the well-documented synergistic effect that addition of a cAMP along with a Ca2+-/ PKC-dependent agonist have on lacrimal gland protein secretion. Indeed, cholinergic agonists activate MAPK, which attenuates protein secretion. When the cAMP pathway is activated, MAPK activity is inhibited; this should alleviate the inhibitory effect that MAPK has on secretion and as a result, protein secretion will be potentiated if both the Ca2 /PKC and the cAMP pathways are activated simultaneously.

The termination of VIP-activated signaling pathways likely includes activation of the cAMP-phosphodiesterase, which converts cAMP to the inactive 5’-AMP. Other signal-terminating mechanisms include desensitization of the VIPR and AC, sequestration of the PKA C subunits by the naturally occurring protein kinase inhibitor (PKI), and activation of protein phosphatases.

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