1. IP 3 R SERCA Ca 2+ BiP Endoplasmic reticulum Ca 2+ = 5x10 -5 M Inactive PERK RyR ATP Ca 2+ Activated PERK Ca 2+ IP 3 GCPR Ligand Receptor-mediated generation of IP 3 and/or activation of voltage-gated channels stimulates ER calcium mobilization and activation of PERK

2. eIF2  [P]/eIF2  Acetylcholine  M Physiological secretegogues activate PERK and eIF2  phosphorylation in the AR42J pancreatic acinar cell line 50nM CCK

3. Pd RTKs bind multiple partners

4. Lipid signaling Membrane phospholipids are used as second messengers PIP 2 IP 3 DAG [Ca 2+ ] PKC PIP 3 PKB /Akt ab a = PI3 kinase b = phospholipase C

5. What happens if I inhibit PLC?

6. UT H2O UT DMSO Ach 60’ Ach 30’ Ach +U 30’ Ach+U 60’ eIF2a[P] eIF2a pERK-1 pERK-2 ERK-1 ERK-2 J Gastrointest Surg. 2001 Nov-Dec;5(6):661-72. Related Articles, Links Cholinergic stimulation of rat acinar cells increases c-fos and c-jun expression via a mitogen-activated protein kinase-dependent pathway. Turner DJ, Cowles RA, Segura BJ, Mulholland MW. Department of Surgery, University of Michigan, Ann Arbor, USA. Acetylcholine release from cholinergic neurons regulates pancreatic exocrine function through pathways that are still under investigation. Pancreatic AR42J acinar cells were studied to determine intracellular calcium ([Ca(2+)](i)) release, enzyme activation, and gene expression in response to the acetylcholine analog carbachol (CCh). CCh stimulated dose-dependent increases in [Ca(2+)](i) that were inhibited by atropine and by specific inhibitors to the muscarinic receptor subtypes m1 and m3. Polymerase chain reaction analysis was performed, which sequenced products corresponding to the m1 and m3 receptor subtypes but not the m2 subtype. CCh also stimulated mitogen- activated protein kinase activity. CCh induced time-and dose-dependent increases in the c-fos and c-jun early-response genes, which were blocked by m1 and m3 inhibition but not by m2 inhibition. PMID: 12086906 [PubMed - indexed for MEDLINE