A large number of G protein coupled receptors (GPCR) utilize cAMP as their second messenger toinduce alterations in cell function. In fact, in the same cell several different GPCR can increase cAMP,leading to the question of how the cell interprets the signals from these receptors differently. Theconcept of cAMP compartmentation, where the second messenger is not generated uniformlythroughout the cell, is readily accepted yet poorly understood. We have found that the enzymes thatsynthesize cAMP, adenylyl cyclases (AC's), are not uniformly distributed through the plasmamembrane. Furthermore, GPCR can preferentially couple to certain AC isoforms due to colocalizationin lipid rafts. While we have made progress in understanding how specific receptors can couple tocertain AC's, little progress has been made in defining the compartments of cAMP inside cells andeven less is known about what cellular responses can be modified by different pools of cAMP. Oneproblem has been that common cell models used in the field lack highly compartmentized cAMP pools.We have found that cultured human airway smooth muscle (HASM) cells express identifiable cAMPcompartments. Furthermore, we can define these compartments based on the isoforms of AC theyexpress.We have observed that signaling by cAMP generated by AC2, but not AC6 or other AC's, leads to theexpression of IL-6 by HASM. Moreover, cAMP generated by AC6, but not by AC2, increasesexpression of somatostatin and stimulates a cell shape change called arborization. Thus, AC2- andAC6-specific responses can be used to define the cAMP signaling compartments in HASM. The goalof this project is to characterize the other components of these two cAMP compartments by usingoverexpression and knockdown of specific AKAP's and PDE's. Novel AC mutants will be used tomanipulate AC localization and function to determine how these pools are assembled. This projectproposes novel, multidisciplinary approaches to define the components responsible for establishingand maintaining cAMP signaling compartments. Results will have broad applicability due to thefundamental nature of cAMP signaling, but because a well-differentiated cell model is used, ourfindings will also have direct relevance to asthma and COPD therapy.GM107094 Ostrom, Rennolds S2.
A large number of hormone and neurotransmitter receptors utilize cAMP to signal inside cells; even when expressed in the same cell; but cause very different responses. This project is designed to understand how cells organize these signals into compartments that can elicit different cellular responses even when a similar biochemical signal is used. Understanding these mechanisms is critical for identifying dysregulated signaling in disease and for designing future therapeutics for a whole host of human disorders.
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| Dessauer, Carmen W; Watts, Val J; Ostrom, Rennolds S et al. (2017) International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases. Pharmacol Rev 69:93-139 |
| Wang, B; Liu, Y; Huang, L et al. (2017) A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism. Mol Psychiatry 22:990-1001 |
| Agarwal, Shailesh R; Miyashiro, Kathryn; Latt, Htun et al. (2017) Compartmentalized cAMP responses to prostaglandin EP2 receptor activation in human airway smooth muscle cells. Br J Pharmacol 174:2784-2796 |
