Neurotransmitter receptors as central regulators of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a near 100% mortality because it is generally detected at an advanced stage and responds poorly to existing therapeutics. This review summarizes current evidence suggesting important roles of neurotransmitter receptors in the regulation of this malignancy. Experimental evidence indicates that the alpha(7)-nicotinic acetylcholine receptor (alpha(7)nAChR) stimulates PDAC via stress neurotransmitter-mediated activation of beta-adrenergic signaling while the alpha(4)beta(2)nAChR inhibits PDAC via GABA-mediated inhibition of adenylyl cyclase activation. In analogy to molecular mechanisms that govern nicotine addiction, chronic exposure to nicotine or its nitrosated derivative nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone render the stimulatory alpha(7)nAChR hyperactive while desensitizing the inhibitory alpha(4)beta(2)nAChR. Accordingly, PDAC intervention strategies should include the diagnosis of unphysiological neurotransmitter levels and aim to restore any imbalance in stimulatory and inhibitory neurotransmitters.

Figure 1. Regulatory functions of the α₇nAChR and the α₄β₂nAChR in the brain

The α₇nAChR acts as an ‘accelerator by stimulating the synthesis and release of the excitatory neurotransmitters noradrenaline (from which adrenaline is formed), dopamine, glutamate and serotonin. Most effects of these neurotransmitters are mediated by GPCRs that activate the enzyme anenylyl cyclase. The α₄β₂nAChR acts as the ‘brake’ by stimulating the synthesis and release of the inhibitory neurotransmitter GABA, which blocks GPCR-mediated activation of adenylyl cyclase by G_i-mediated activity of the GABA-B-R. GABA-B-R: GABA-B receptor; GPCR: G-protein-coupled receptor; nAChR: Nicotinic acetylcholine receptor.

Figure 2. Working model of changes in nAChR functions in the brain associated with nicotine addiction

Chronic exposure to nicotine upregulates the stimulatory α₇nAChR without concomittant receptor desensitization, whereas the inhibitory α₄β₂nAChR undergoes long-term desensitization accompanied by upregulation. The resulting predominance of excitatory neurotransmitters and relative deficiency in inhibitory GABA lead to symptoms associated with nicotine addiction and craving. GABA-B-R: GABA-B receptor; GPCR: G-protein-coupled receptor; nAChR: Nicotinic acetylcholine receptor.

Figure 3. Working model of the regulation of pancreatic ductal adenocarcinoma by neurotransmitters, their receptors and downstream effectors

Chronic exposure to nicotinic agonists in tobacco products and in the human environment cause nAChR changes analogous to those in the nicotine-addicted brain (compare with Figure 2). The resulting predominance of stimulatory adenylyl cylase-dependent signaling and relative deficiency in inhibitory GABA leads to the selective activation of cell proliferation, migration and angiogenesis while inhibiting apoptosis. In addition, psychological stress activates this cancer-stimulating cascade by causing the release of acetylcholine that activates α₇nAChRs in the nervous system and nAChRs containing the α₃-or α₅-subunits in the hypothalamus and adrenal medulla, resulting in the release of noradrenaline and adrenaline into the bloodstream. AA: Arachidonic acid; AKT: Serine threonine protein kinase B; βAR: β-adrenergic receptor; CREB: cAMP response element binding; EGFR: EGF receptor; GABA-B-R: GABA-B receptor; nAChR: Nicotinic acetylcholine receptor; NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; PKA: Protein kinase A.