Phosphodiesterases and compartmentalized cAMP signalling in the heart

A key feature of the cAMP/cAMP-dependent protein kinase (PKA) transduction system is the compartmentalisation of its signalling enzymes and effectors. Given the large diversity of PKA targets within cardiac cells a precisely regulated and confined activity of such signalling pathway is essential for specificity of response. This appears to be achieved through the generation of local pools of high cAMP and activation of PKA at discrete subcellular locations. Phosphodiesterases (PDEs) are the only route for degrading cAMP and are thus poised to regulate intracellular cAMP gradients. Their spatial confinement to discrete compartments and functional coupling to individual receptors provides an efficient way to control local [cAMP](i) in a stimulus-specific manner. A better understanding of the distinctive role that individual PDEs play in shaping the cAMP signal in heart cells may lead to the development of new strategies for selective pharmacologic manipulation of cAMP signalling in defined functional domains.     

Dynamic regulation of cAMP synthesis through anchored PKA-adenylyl cyclase V/VI complexes

Spatiotemporal organization of cAMP signaling begins with the tight control of second messenger synthesis. In response to agonist stimulation of G protein-coupled receptors, membrane-associated adenylyl cyclases (ACs) generate cAMP that diffuses throughout the cell. The availability of cAMP activates various intracellular effectors, including protein kinase A (PKA). Specificity in PKA action is achieved by the localization of the enzyme near its substrates through association with A-kinase anchoring proteins (AKAPs). Here, we provide evidence for interactions between AKAP79/150 and ACV and ACVI. PKA anchoring facilitates the preferential phosphorylation of AC to inhibit cAMP synthesis. Real-time cellular imaging experiments show that PKA anchoring with the cAMP synthesis machinery ensures rapid termination of cAMP signaling upon activation of the kinase. This protein configuration permits the formation of a negative feedback loop that temporally regulates cAMP production.     

Molecular mechanisms of feedback inhibition of protein kinase A on intracellular cAMP accumulation

The cAMP-protein kinase A (PKA) pathway is a major signalling pathway in the yeast Saccharomyces cerevisiae, but also in many other eukaryotic cell types, including mammalian cells. Since cAMP plays a crucial role as second messenger in the regulation of this pathway, its levels are strictly controlled, both in the basal condition and after induction by agonists. A major factor in the down-regulation of the cAMP level after stimulation is PKA itself. Activation of PKA triggers feedback down-regulation of the increased cAMP level, stimulating its return to the basal concentration. This is accomplished at different levels. The best documented mechanisms are: inhibition of cAMP synthesis by down-regulation of adenylate cyclase and/or its regulatory proteins, stimulation of cAMP breakdown by phosphodiesterases and spatial regulation of cAMP levels in the cell by A-Kinase Anchoring Proteins (AKAPs). In this review we describe these processes in detail for S. cerevisiae, for cells of mammals and selected other organisms, and we hint at other possible targets for feedback regulation of intracellular cAMP levels.     

A-kinase anchoring proteins interact with phosphodiesterases in T lymphocyte cell lines

The cAMP protein kinase A (PKA) pathway in T cells conveys an inhibitory signal to suppress inflammation. This study was performed to understand the mechanisms involved in cAMP-mediated signaling in T lymphocytes. A-kinase anchoring proteins (AKAPs) bind and target PKA to various subcellular locations. AKAPs also bind other signaling molecules such as cyclic nucleotide phosphodiesterases (PDEs) that hydrolyze cAMP in the cell. PDE4 and PDE7 have important roles in T cell activation. Based on this information, we hypothesized that AKAPs associate with PDEs in T lymphocytes. Immunoprecipitation of Jurkat cell lysates with Abs against both the regulatory subunit of PKA (RIIalpha) and specific AKAPs resulted in increased PDE activity associated with RIIalpha and AKAP95, AKAP149, and myeloid translocation gene (MTG) compared with control (IgG). Immunoprecipitation and pull-down analyses demonstrate that PDE4A binds to AKAP149, AKAP95, and MTG, but not AKAP79, whereas PDE7A was found to bind only MTG. Further analysis of MTG/PDE association illustrated that PDE4A and PDE7A bind residues 1-344 of MTG16b. Confocal analysis of HuT 78 cells stained with anti-PDE7A showed overlapping staining patterns with the Golgi marker GM130, suggesting that PDE7A is located in the Golgi. The staining pattern of PDE7A also showed similarity to the staining pattern of MTG, supporting the immunoprecipitation data and suggesting that MTG may interact with PDE7A in the Golgi. In summary, these data suggest that AKAPs interact with both PKA and PDE in T lymphocytes and thus are a key component of the signaling complex regulating T cell activation.     

Spatial organisation of AKAP18 and PDE4 isoforms in renal collecting duct principal cells

A plethora of stimuli including hormones and neurotransmitters mediate a rise of the cellular level of cAMP and thereby activation of protein kinase A (PKA). PKA phosphorylates and thereby modulates the activity of a wide range of cellular targets. It is now appreciated that different stimuli induce the activation of PKA at specific sites where the kinase phosphorylates particular substrates in close proximity. The tethering of PKA to cellular compartments is facilitated by A kinase-anchoring proteins (AKAPs). The incorporation of phosphodiesterases (PDEs) into AKAP-based signalling complexes provides gradients of cAMP that regulate PKA activity locally. An example for a process depending on compartmentalised cAMP/PKA signalling is the arginine-vasopressin (AVP)-mediated water reabsorption in renal collecting duct principal cells. Upon activation through AVP, PKA phosphorylates the water channel aquaporin-2 (AQP-2) located on intracellular vesicles. The phosphorylation triggers the redistribution of AQP2 to the plasma membrane. AKAP-anchored PKA has been shown to be involved in AQP2 shuttling. Here, AKAP18 isoforms and members of the PDE4 family of PDEs are shown to be differentially localised in renal principal cells.     

Developmentally acquired PKA localisation in mouse oocytes and embryos

Localisation of Protein Kinase A (PKA) by A-Kinase Anchoring Proteins (AKAPs) is known to coordinate localised signalling complexes that target cAMP-mediated signalling to specific cellular sub-domains. The cAMP PKA signalling pathway is implicated in both meiotic arrest and meiotic resumption, thus spatio-temporal changes in PKA localisation during development may determine the oocytes response to changes in cAMP. In this study we aim to establish whether changes in PKA localisation occur during oocyte and early embryo development.Using fluorescently-labelled PKA constructs we show that in meiotically incompetent oocytes PKA is distributed throughout the cytoplasm and shows no punctuate localisation. As meiotic competence is acquired, PKA associates with mitochondria. Immature germinal vesicle (GV) stage oocytes show an aggregation of PKA around the GV and PKA remains co-localised with mitochondria throughout oocyte maturation. After fertilisation, the punctuate, mitochondrial distribution was lost, such that by the 2-cell stage there was no evidence of PKA localisation. RT-PCR and Western blotting revealed two candidate AKAPs that are known to be targeted to mitochondria, AKAP1 and D-AKAP2. In summary these data show a dynamic regulation of PKA localisation during oocyte and early embryo development.     

AKAP signaling complexes: getting to the heart of the matter

Subcellular compartmentalization of protein kinases and phosphatases through their interaction with A-kinase anchoring proteins (AKAPs) provides a mechanism to control signal transduction events at specific sites within the cell. Recent findings suggest that these anchoring proteins dynamically assemble different cAMP effectors to control the cellular actions of cAMP spatially and temporally. In the heart, signaling events such as the onset of cardiac hypertrophy are influenced by muscle-specific mAKAP signaling complexes that target protein kinase A (PKA), the cAMP-responsive guanine-nucleotide exchange factor EPAC and cAMP-selective phosphodiesterase 4 (PDE4). Mediation of signaling events by AKAPs might also have a role in the control of lipolysis in adipocytes, where insulin treatment reduces the association of AKAPs with G-protein-coupled receptors. These are only two examples of how AKAPs contribute to specificity in cAMP signaling. This review will explore recent development that illustrates the role of multiprotein complexes in the regulation of cAMP signaling.     

Identification and characterization of myeloid translocation gene 16b as a novel a kinase anchoring protein in T lymphocytes

Increased levels of intracellular cAMP inhibit T cell activation and proliferation. One mechanism is via activation of the cAMP-dependent protein kinase (PKA). PKA is a broad specificity serine/threonine kinase whose fidelity in signaling is maintained through interactions with A kinase anchoring proteins (AKAPs). AKAPs are adaptor/scaffolding molecules that convey spatial and temporal localization to PKA and other signaling molecules. To determine whether T lymphocytes contain AKAPs that could influence the inflammatory response, PBMCs and Jurkat cells were analyzed for the presence of AKAPs. RII overlay and cAMP pull down assays detected at least six AKAPs. Western blot analyses identified four known AKAPs: AKAP79, AKAP95, AKAP149, and WAVE. Screening of a PMA-stimulated Jurkat cell library identified two additional known AKAPs, AKAP220 and AKAP-KL, and one novel AKAP, myeloid translocation gene 16 (MTG16b). Mutational analysis identified the RII binding domain in MTG16b as residues 399-420, and coimmunoprecipitation assays provide strong evidence that MTG16b is an AKAP in vivo. Immunofluorescence and confocal microscopy illustrate distinct subcellular locations of AKAP79, AKAP95, and AKAP149 and suggest colocalization of MTG and RII in the Golgi. These experiments represent the first report of AKAPs in T cells and suggest that MTG16b is a novel AKAP that targets PKA to the Golgi of T lymphocytes.     

Cyclic nucleotide phosphodiesterase 3 signaling complexes

The superfamily of cyclic nucleotide phosphodiesterases is comprised of 11 gene families. By hydrolyzing cAMP and cGMP, PDEs are major determinants in the regulation of intracellular concentrations of cyclic nucleotides and cyclic nucleotide-dependent signaling pathways. Two PDE3 subfamilies, PDE3A and PDE3B, have been described. PDE3A and PDE3B hydrolyze cAMP and cGMP with high affinity in a mutually competitive manner and are regulators of a number of important cAMP- and cGMP-mediated processes. PDE3B is relatively more highly expressed in cells of importance for the regulation of energy homeostasis, including adipocytes, hepatocytes, and pancreatic β-cells, whereas PDE3A is more highly expressed in heart, platelets, vascular smooth muscle cells, and oocytes. Major advances have been made in understanding the different physiological impacts and biochemical basis for recruitment and subcellular localizations of different PDEs and PDE-containing macromolecular signaling complexes or signalosomes. In these discrete compartments, PDEs control cyclic nucleotide levels and regulate specific physiological processes as components of individual signalosomes which are tethered at specific locations and which contain PDEs together with cyclic nucleotide-dependent protein kinases (PKA and PKG), adenylyl cyclases, Epacs (guanine nucleotide exchange proteins activated by cAMP), phosphoprotein phosphatases, A-Kinase anchoring proteins (AKAPs), and pathway-specific regulators and effectors. This article highlights the identification of different PDE3A- and PDE3B-containing signalosomes in specialized subcellular compartments, which can increase the specificity and efficiency of intracellular signaling and be involved in the regulation of different cAMP-mediated metabolic processes.     

Dynamic anchoring of PKA is essential during oocyte maturation

In the final stages of ovarian follicular development, the mouse oocyte remains arrested in the first meiotic prophase, and cAMP-stimulated PKA plays an essential role in this arrest. After the LH surge, a decrease in cAMP and PKA activity in the oocyte initiates an irreversible maturation process that culminates in a second arrest at metaphase II prior to fertilization. A-kinase anchoring proteins (AKAPs) mediate the intracellular localization of PKA and control the specificity and kinetics of substrate phosphorylation. Several AKAPs have been identified in oocytes including one at 140 kDa that we now identify as a product of the Akap1 gene. We show that PKA interaction with AKAPs is essential for two sequential steps in the maturation process: the initial maintenance of meiotic arrest and the subsequent irreversible progression to the polar body extruded stage. A peptide inhibitor (HT31) that disrupts AKAP/PKA interactions stimulates oocyte maturation in the continued presence of high cAMP. However, during the early minutes of maturation, type II PKA moves from cytoplasmic sites to the mitochondria, where it associates with AKAP1, and this is shown to be essential for maturation to continue irreversibly.     

A-kinase anchoring proteins: scaffolding proteins in the heart

The pleiotropic cyclic nucleotide cAMP is the primary second messenger responsible for autonomic regulation of cardiac inotropy, chronotropy, and lusitropy. Under conditions of prolonged catecholaminergic stimulation, cAMP also contributes to the induction of both cardiac myocyte hypertrophy and apoptosis. The formation of localized, multiprotein complexes that contain different combinations of cAMP effectors and regulatory enzymes provides the architectural infrastructure for the specialization of the cAMP signaling network. Scaffolds that bind protein kinase A are called "A-kinase anchoring proteins" (AKAPs). In this review, we discuss recent advances in our understanding of how PKA is compartmentalized within the cardiac myocyte by AKAPs and how AKAP complexes modulate cardiac function in both health and disease.     

AKAP signalling complexes: focal points in space and time

Multiprotein signalling networks create focal points of enzyme activity that disseminate the intracellular action of many hormones and neurotransmitters. Accordingly, the spatio-temporal activation of protein kinases and phosphatases is an important factor in controlling where and when phosphorylation events occur. Anchoring proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize various enzymes that are regulated by second messengers.     

AKAP3 selectively binds PDE4A isoforms in bovine spermatozoa

Cyclic AMP plays an important role in regulating sperm motility and acrosome reaction through activation of cAMP-dependent protein kinase A (PKA). Phosphodiesterases (PDEs) modulate the levels of cyclic nucleotides by catalyzing their degradation. Although PDE inhibitors specific to PDE1 and PDE4 are known to alter sperm motility and capacitation in humans, little is known about the role or subcellular distribution of PDEs in spermatozoa. The localization of PKA is regulated by A-kinase anchoring proteins (AKAPs), which may also control the intracellular distribution of PDE. The present study was undertaken to investigate the role and localization of PDE4 during sperm capacitation. Addition of Rolipram or RS25344, PDE4-specific inhibitors significantly increased the progressive motility of bovine spermatozoa. Immunolocalization techniques detected both PDE4A and AKAP3 (formerly known as AKAP110) in the principal piece of bovine spermatozoa. The PDE4A5 isoform was detected primarily in the Triton X-100-soluble fraction of caudal epididymal spermatozoa. However, in ejaculated spermatozoa it was seen primarily in the SDS-soluble fraction, indicating a shift in PDE4A5 localization into insoluble organelles during sperm capacitation. AKAP3 was detected only in the SDS-soluble fraction of both caudal and ejaculated sperm. Immunoprecipitation experiments using COS cells cotransfected with AKAP3 and either Pde4a5 or Pde4d provide evidence that PDE4A5 but not PDE4D interacts with AKAP3. Pulldown assays using sperm cell lysates confirm this interaction in vitro. These data suggest that AKAP3 binds both PKA and PDE4A and functions as a scaffolding protein in spermatozoa to regulate local cAMP concentrations and modulate sperm functions.     

Dynamics of phosphodiesterase-induced cAMP dissociation from protein kinase A: Capturing transient ternary complexes by HDXMS

cAMP signaling is a fundamental cellular process necessary for mediating responses to hormonal stimuli. In contrast to cAMP-dependent activation of protein kinase A (PKA), an important cellular target, far less is known on termination in cAMP signaling, specifically how phosphodiesterases (PDEs) facilitate dissociation and hydrolysis of bound cAMP. In this study, we have probed the dynamics of a ternary complex of PKA and a PDE–RegA with an excess of a PDE-nonhydrolyzable cAMP analog, Sp-cAMPS by amide hydrogen/deuterium exchange mass spectrometry (HDXMS). Our results highlight how HDXMS can be used to monitor reactions together with mapping conformational dynamics of transient signaling complexes. Our results confirm a two-state model for active RegA-mediated dissociation of bound cAMP. Further, our results reveal that Sp-cAMPS and RegA mediate mutually exclusive interactions with the same region of PKA and at specific concentrations of Sp-cAMPS, RegA is capable of blocking Sp-cAMPS reassociation to PKA. This provides a molecular basis for how PDEs modulate levels of intracellular cAMP so that PKA is better suited to responding to fluxes rather than constant levels of cAMP. This study underscores how HDXMS can be a powerful tool for monitoring reactions together with mapping conformational dynamics in signaling proteins. This article is part of a Special Issue entitled: Mass spectrometry in structural biology.     

cAMP-PKA signaling to the mitochondria: protein scaffolds, mRNA and phosphatases

Energy metabolism and, specifically, the coupling of mitochondria to growth and survival is controlled by the cAMP-PKA pathway in yeast. In higher eukaryotes, cAMP signaling originating at the plasma membrane is distributed to different subcellular districts by cAMP waves received by PKA bound to PKA anchor proteins (AKAPs) tethered to these compartments. This review focuses on the subgroup of AKAPs that anchor PKA to the mitochondrial outer membrane (mtAKAPs). Only PKA anchored to mtAKAPs can efficiently transmit cAMP signals to mitochondria. mtAKAP complexes are remarkably heterogeneous. In addition to PKA regulatory subunits, they may include mRNAs, tyrosine phosphatase(s) and tyrosine kinase(s). Selective regulation of these components by cAMP-PKA integrates various signal transduction pathways and can determine which subcellular compartment receives the signal. Unveiling the interactions among the components of these large complexes will shed light on how cAMP and PKA regulate vital mitochondrial processes.     

Targeting of an A kinase-anchoring protein, AKAP79, to an inwardly rectifying potassium channel, Kir2.1

Protein kinase A (PKA) is targeted to discrete subcellular locations close to its intended substrates through interaction with A kinase-anchoring proteins (AKAPs). Ion channels represent a diverse and important group of kinase substrates, and it has been shown that membrane targeting of PKA through association with AKAPs facilitates PKA-mediated phosphorylation and regulation of several classes of ion channel. Here, we investigate the effect of AKAP79, a membrane-associated multivalent-anchoring protein, upon the function and modulation of the strong inwardly rectifying potassium channel, Kir2.1. Functionally, the presence of AKAP79 enhanced the response of Kir2.1 to elevated intracellular cAMP, suggesting a requirement for a pool of PKA anchored close to the channel. Antibodies directed against a hemagglutinin epitope tag on Kir2.1 coimmunoprecipitated AKAP79, indicating that the two proteins exist together in a complex within intact cells. In support of this, glutathione S-transferase fusion proteins of both the intracellular N and C domains of Kir2.1 isolated AKAP79 from cell lysates, while glutathione S-transferase alone failed to interact with AKAP79. Together, these findings suggest that AKAP79 associates directly with the Kir2.1 ion channel and may serve to anchor kinase enzymes in close proximity to key channel phosphorylation sites.     

Selectivity in Enrichment of cAMP-dependent Protein Kinase Regulatory Subunits Type I and Type II and Their Interactors Using Modified cAMP Affinity Resins

cAMP regulates cellular functions primarily by activating PKA. The involvement of PKAs in various signaling pathways occurring simultaneously in different cellular compartments necessitates stringent spatial and temporal regulation. This specificity is largely achieved by binding of PKA to protein scaffolds, whereby a distinct group of proteins called A kinase anchoring proteins (AKAPs) play a dominant role. AKAPs are a diverse family of proteins that all bind via a small PKA binding domain to the regulatory subunits of PKA. The binding affinities between PKA and several AKAPs can be different for different isoforms of the regulatory subunits of PKA. Here we employ a combination of affinity chromatography and mass spectrometry-based quantitative proteomics to investigate specificity in PKA-AKAP interactions. Three different immobilized cAMP analogs were used to enrich for PKA and its interacting proteins from several systems; HEK293 and RCC10 cells and rat lung and testis tissues. Stable isotope labeling was used to confidently identify and differentially quantify target proteins and their preferential binding affinity for the three different cAMP analogs. We were able to enrich all four isoforms of the regulatory subunits of PKA and concomitantly identify more than 10 AKAPs. A selective enrichment of the PKA RI isoforms could be achieved; which allowed us to unravel which AKAPs bind preferentially to the RI or RII regulatory domains of PKA. Of the twelve AKAPs detected, seven preferentially bound to RII, whereas the remaining five displayed at least dual specificity with a potential preference for RI. For some of these AKAPs our data provide the first insights into their specificity.cAMP is an ubiquitous second messenger that transduces signals from a variety of hormones, neurotransmitters, and inflammatory mediators to regulate a large number of key cellular processes. cAMP can influence cell growth, differentiation, and movement as well as regulating specialized actions unique to specific cell types. The principal target of cAMP is cAMP-dependent protein kinase (PKA)¹. Several other proteins such as cyclic nucleotide gated ion channels (1), phosphodiesterases (PDE) (2), and guanine nucleotide exchange factors (Epac) (3) bind cAMP. Interestingly, localized pools of cAMP regulate defined physiological events. It appears that for such events a supramolecular complex is required that comprises of the appropriate effector system together with signal termination enzymes such as PDEs and phosphatases that are sequestered by scaffolding proteins (4). Some of the best described scaffolding proteins are the so-called A-kinase anchoring proteins (AKAPs), which all bind specifically to the N-terminal dimerization domain of the PKA regulatory domain. The organization of a few of these individual supramolecular complexes containing PKA/AKAPs/PDE etc. has been described (4); numerous more of such complexes are expected to exist.The regulatory domains of mammalian PKAs exist in several isoforms such as RIα, RIβ, RIIα, and RIIβ, which are all encoded by separate genes. The two major isoforms i.e. RI and RII differ in molecular weight, isoelectric point, amino acid sequence, phosphorylation status, tissue distribution, and sub-cellular localization. RI and RII subunits are known to bind to AKAPs with distinct levels of affinity adding another level of intracellular organization for PKA and also facilitating the diversity of the cAMP-mediated signal transduction pathways. Although the PKA-R isoforms differ in functionality, they share a similar overall organization i.e. a dimerization domain, the catalytic subunits inhibitor region, and two cAMP binding domains. The two cAMP binding domains differ in cAMP binding kinetics and are known as site A and site B, respectively (5). Both sites share considerable sequence identity, as a result of a tandem gene duplication, and have conserved phosphate binding cassettes that can be considered as signature motif for cAMP binding. The relative orientation of these two sites is nonetheless, quite different in RI and RII. Additionally, A and B sites have different binding affinity to cAMP derivatives. Site A has a preference for N6-substituted analogs whereas site B is preferred by C2- and C8-substituted analogs (6).PKA has been studied extensively (7, 8). One of the important goals therein is to develop different cAMP analogs that can result in specific binding, activation, and/or inhibition for each individual cAMP interaction site of the RI and RII isoforms (9). This can help to decipher in detail specific cyclic nucleotide signaling pathways (10). To fully interpret such pathways, analogs should ideally not cross-activate (or inhibit) with other cAMP-regulated proteins such as the before mentioned PDEs, Epac, cyclic nucleotide gated ion channels, and the cGMP-dependent protein kinase (PKG). Although the latter is mainly activated by cGMP, it also binds to cAMP (11, 12). It has been suggested that cGMP and cAMP can cross-activate their respective kinases (13). This cross-talk between PKA and PKG hampers, to some degree, the study of these proteins individually, as dissecting the individual pathways of PKA and PKG requires specific binders, activators, or inhibitors (9, 14). Compared with PKA, PKG is involved in quite different signaling pathways, such as the well characterized nitric oxide-mediated relaxation of smooth muscle cells (15).The development of synthetic cAMP and cGMP analogs as tools to unravel specific signal transduction pathways requires the sensitive identification and characterization of their cyclic nucleotide interacting proteins. These proteins are typically relatively low abundant, and therefore specific enrichment techniques are essential to study these so-called cyclic-nucleotide interactomes. In recent years such affinity enrichment techniques have been coupled to sensitive mass spectrometric identification of the enriched proteins, nowadays often referred to as chemical proteomics. Chemical proteomics using small molecules as baits, i.e. messenger molecules, drugs, or metabolites, becomes more and more widely used to selectively isolate target proteins from whole cell lysates enabling the analysis of protein subcomplexes and/or signaling pathways (16, 17).In the present study we compare the properties of three cAMP analogs immobilized individually on agarose beads, for enrichment, isolation, and detection of cyclic nucleotide interacting proteins and their interaction partners, like AKAPs, directly from a crude lysate of cells and tissue. To quantify differential affinity, we use a common strategy in proteomics, namely stable isotope labeling, whereby we introduce the label via reductive amination (18–20). Most interestingly, a very selective enrichment of PKA RI isoforms can be achieved by using cAMP-agarose beads in which the hydroxyl group at the 2′ position on the ribose was replaced with a methoxyl group. This allows us to distinguish, which AKAPs bind preferentially to the RI or RII isoforms. Therefore, this approach provides an elegant tool to further decipher specific cyclic nucleotide signaling pathways.     

A型激酶锚定蛋白及其复合物结构与功能

A型激酶锚定蛋白(A-kinase anchoring proteins,AKAPs)是一类结构不同而功能相关的蛋白家族,其主要功能是将cAMP依赖性蛋白激酶A（PKA）锚定于特定的亚细胞结构.PKA是第二信使cAMP的主要效应器,而AKAPs在靶向定位和调节PKA介导的磷酸化事件方面扮演重要角色. AKAPs更为重要的功能是与多种信号分子形成信号复合物,从时间和空间上整合cAMP-PKA和其他信号途径.本文将对AKAPs及其信号复合物的结构特点和参与细胞信号转导的功能机制及其研究现状进行概述.