A‐kinase anchoring proteins: cAMP compartmentalization in neurodegenerative and obstructive pulmonary diseases

Abstract

The universal second messenger cAMP is generated upon stimulation of Gs protein-coupled receptors, such as the β2-adreneoceptor, and leads to the activation of PKA, the major cAMP effector protein. PKA oscillates between an on and off state and thereby regulates a plethora of distinct biological responses. The broad activation pattern of PKA and its contribution to several distinct cellular functions lead to the introduction of the concept of compartmentalization of cAMP. A-kinase anchoring proteins (AKAPs) are of central importance due to their unique ability to directly and/or indirectly interact with proteins that either determine the cellular content of cAMP, such as β2-adrenoceptors, ACs and PDEs, or are regulated by cAMP such as the exchange protein directly activated by cAMP. We report on lessons learned from neurons indicating that maintenance of cAMP compartmentalization by AKAP5 is linked to neurotransmission, learning and memory. Disturbance of cAMP compartments seem to be linked to neurodegenerative disease including Alzheimer's disease. We translate this knowledge to compartmentalized cAMP signalling in the lung. Next to AKAP5, we focus here on AKAP12 and Ezrin (AKAP78). These topics will be highlighted in the context of the development of novel pharmacological interventions to tackle AKAP-dependent compartmentalization. AbbreviationsAKAP, A-kinase anchoring protein; AKIP, A-kinase interacting protein; APP, amyloid precursor protein; CREB, cAMP response element-binding protein; CSE, cigarette smoke extract; Epac, exchange factor directly activated by cAMP; GSKIP, GSK3β interaction protein; LTD, long-term depression; MAGUK, membrane-associated guanylate kinase; MAP2, microtubule-associated protein 2; MLC, myosin light chain; PKI, PK inhibitor; PP2B/CaN, phosphatase 2B/calcineurin (also PPP3); PSD, postsynaptic density; RhoGDI, Rho guanine-nucleotide-dissociation inhibitor; RI, regulatory subunit I of PKA; RII, regulatory subunit II of PKA; SKIP, sphingosine kinase interacting protein BJP British Journal of Pharmacology

A-kinase-anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle

“…CAMP and its effectors are under tight spatiotemporal control by a family of scaffolding proteins with over 50 members called A-kinaseanchoring proteins (AKAPs) (32,37,38). AKAPs regulate diverse cellular processes, including release of inflammatory cytokines from cardiomyocytes and alveolar macrophages (8,21).…”

“…AKAP5 and AKAP12 directly interact with the ␤ 2 -adrenoceptor (5,11,16,32,39). Thus we hypothesized that alterations in AKAP5 and AKAP12 expression may affect the anti-inflammatory effects of ␤ 2 -agonists on cigarette smokeinduced inflammatory responses.…”

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

“…In addition, altered cAMP signaling is associated with a plethora of neurodegenerative diseases such as Alzheimer´s, Parkinson´s and Huntington´s disease, recently reviewed by Poppinga et al [161]. This points out the obvious physiological relevance of cAMP, PKA and AKAPs in the healthy neuronal system as well as in disease.…”

“…cAMP compartmentalization is involved in important features of COPD such as inflammation and airway remodeling. ASM cells are important players in these processes (recently reviewed in [161]). They switch phenotype between a proliferative and contractile state upon stimulation, e.g.…”

“…AKAPs play roles in many more cellular processes whose dysregulation leads to disease. They are involved in complex mechanisms such as memory formation and blood pressure control [161,262,263] and tether different protein assemblies to various subcellular compartments [264]. Thus AKAPs are a rich source to be considered as pharmacological targets.…”