Development - PACAP signaling in neural cells

PACAP signaling in neural cells

PACAP is a member of the secretin superfamily of neuropeptides expressed in both the brain and peripheral nervous system. PACAP acts via specific PACAP receptor 1 to promote neurotrophic and neurodevelopmental effects on neural cells [1], [2], [3].

PACAP receptor 1 belongs to the family of G-protein-coupled receptors. It acts via G-protein alpha-s to activate Adenylate cyclase type I [4], [5], and via G-protein alpha-q/11 to activate PLC-beta [6], [7], [8], [9], [10].

Activation of Adenylate cyclase type I by PACAP signaling leads to enhanced Cyclic AMP production and activation of PKA-reg (cAMP-dependent)/ PKA-cat (cAMP-dependent). PKA-cat (cAMP-dependent) activates RAP-1A [2], [3], [11]. PACAP also activates RAP-1A in a PKA-independent manner via Cyclic AMP-mediated activation of cAMP-GEFI and cAMP-GEFII [3], [12], [13]. RAP-1A triggers B-Raf)/ MEK1(MAP2K1), MEK2(MAP2K2)/ ERK1/2 cascade that leads to phosphorylation of two proteins, Elk-1) and CREB1. p90RSK2(RPS6KA3) most likely phosphorylates CREB1 [14], [15]) [5], [11], [16]. CREB1 coupled to ATF-1 induces expression of the TY3H [2], [17]. Activation of Elk-1 and CREB1 by PACAP signaling stimulates neurite outgrowth (see neuron projection development) and promotes cell differentiation of PC12, granule cells, and neural stem cells [2], [5], [18].

PACAP stimulation of PLC-beta activity leads to 1,2-Diacyglycerol and IP3 production and Ca('2+) release from internal stores [7], [8], [9]. These second messengers activate conventional forms of cPKC (conventional). cPKC (conventional) induces B-Raf/ MEK1(MAP2K1), MEK2(MAP2K2)/ ERK1/2 cascade, leading to activation of CREB1 and Elk-1 and stimulation of differentiation of the neural cells (see neurogenesis) [5], [19], [20], [21].

PACAP-mediated activation of CREB1 leads to enhanced expression of the c-Fos [1], [22], [23], [24], [25]. c-Fos induces Bcl-2 transcription [26]. Bcl-2 prevents Bax -mediated release of the Cytochrome c from mitochondria and suppresses activation of Caspase-3 [25]. In addition, PACAP-stimulated PKA-cat (cAMP-dependent) suppresses Caspase-3 activity probably via phosphorylation of Caspase-9 [25], [27], [28], [29], [30]. This leads to enhanced survival of neural cells (see anti-apoptosis [3], [28].

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References:

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