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3.b2AR & A2BR Mediated CREB

Introduction to P38 Signalling in VSMCs

Hypertension is one of the major health concerns globally [7]. The cardiovascular system and kidney regulation are effective in the management and action of hypertension, a foundation role of the contractile state of vascular smooth muscle (VSM) has also been discussed in the context that it regulates the blood vessels’ radii, thus influencing the peripheral resistance [8]. There is an increase in the adrenergic tone from the stress and a chronic stimulation of the β1 adrenergic receptors (*****) Two types of βAR (β Adrenergic Receptors) present in VSMC and we suspect from our previous work that 80% of the total number of receptors present are β2 with 20% β1. (****). The contractile state of the VSMs is regulated by multiple agnostics that possess this ability. Many of these agonists transmit their signals via GPCRs (G-protein-coupled receptors). The GPCR superfamily is a primary target to be considered for pharmaceutical therapies [10]. Moreover, it is one of the largest protein families. GPCRs have a common structure with seven-transmembrane spanning domains, and they activate the heterotrimeric G-proteins.

The activation of these G-proteins subsequently results in the transduction of the extracellular signal to the intracellular effector molecules [11]. Additionally, there are four different major subclasses of G-proteins which include Gαs (stimulatory), Gαi/o (inhibitory), Gαq and Gα12/13. The coupling of GPCRs to these different subclasses of G-proteins allows for very diverse intracellular signalling events [12]. For example, activation of Gαs stimulates adenylate cyclase (adenylyl cyclase), which leads to the formation of the second messenger cAMP. Mainly, cAMP  mediates its actions through PKA (protein kinase A), exchange protein activated by cAMP (EPAC) [2]. Moreover, it binds to and activates the transcription factor cAMP response element-binding (CREB) protein [4]. The A2a and A2b pathways of signalling are prominent in the GPCR signalling and are upregulated for specific responses that function to trigger the cAMP pathway. Both A2A and A2B receptors are said to be expressed in VSMC but our work suggests that only A2B are expression and functional in our cells (*****). 

CREB is a component of the family of proteins that function as transcription elements and is localised in the nucleus of cells [48]. The CREB is critical for stimulus-transcription coupling, which is the transmission of events that take place within the cell membrane and their activity leads to alterations in gene expression within the nucleus [49]. The role of CREB has been identified in the regulation of VMSC proliferation (*). The CREB levels are high in the differentiated VMSC but a decrease is observed during phenotypic modulation (*). Therefore, the role of CREB is under lens for representation in one of the important mechanisms associated with cAMP-dependent cellular responses. This action is further validated by research where CREB inhibition via RNA interference has been known to induce VSMC proliferation (**). The CREB (cAMP response element-binding) signalling is important in the proliferation and migration in VSMC that are essential in vascular remodelling [47]. 

Besides, MAPKs (mitogen-activated protein kinases) are a family of ubiquitous protein serine/threonine kinases which respond to a range of extracellular stimuli and mediate intracellular signal transduction [71]. Furthermore, dual phosphorylation of conserved threonine and tyrosine residues is triggered as a result of the process where extracellular signals are obtained from direct upstream activators called MAPK kinases (MKKs) [72]. Consequently, MAPKs relay their signals by phosphorylating downstream substrates on threonine or serine residues adjacent to proline residues [73]. MAPKs are active in the proliferation, migration, and hypertrophy of VSMCs, processes that are central to the pathogenesis of vascular diseases [74]. MAPK consists of three key main subtypes: first, p38 MAPK, second, ERK and third JNK [75] However, recent evidence also suggests CREB phosphorylation by MAPK signalling pathway (***). The binding of cAMP to the regulatory protein subunit of protein kinase A leads to the disassociation and movement of the catalytic subunit of PKA for the phosphorylation of CREB. The activation of CREB has also been reported by NGF at serine133 through p38 MAPK (***).

 Also, various transcription factors with various activities are phosphorylated and subsequently triggered by p38mitogen-activated protein kinase (MAPK) [76]. However, several experiments have shown that P38 plays a key role in modulating signal pathways implicated in cellular events contributing to restenosis [75]. Selective pharmacological inhibition of p38MAPK can thus effectively minimise neo-intimal hyperplasia following vascular wall injury [77]. SB203580 is a selective p38 MAPKs inhibitor confirmed to restrict the proliferation of VSMC [78]. Furthermore, extracellular signal-regulated kinase (ERK) phosphorylates the intracellular substrates in the cytoplasm, of which cytoskeletal and adhesion junction proteins, as well as apoptotic and cell cycle regulators, stand out [79]. ERK plays a central role in cardiac physiology as proliferation and cell growth play important processes for heart development [80]. Crucially, ERK molecules are implicated throughout many forms of progression to heart failure and cardiac hypertrophy [81]. Studies theorise thatPD98059 is a selective inhibitor and potent of MAP kinase kinases (MAPKK), also specific inhibitors of ERK kinase [82].

Whereas, the other category plays a major factor by regulating signal transduction through a wide diverse group of cell surface receptors in several cellular environments is Src family of the protein tyrosine kinases (SFKs)[83]. FurthermorePP1 (4-Amino-5-(4-methyl phenyl)-7-(t-butyl) pyrazolo[3,4-d]- pyrimidine) was identified as a Src-selective tyrosine kinase inhibitor and has been used extensively to investigate signalling pathways involving Src kinases [84]. potential links between receptor activation and CREB phosphorylation, as also a link between receptor activation and p38 phosphorylation. Furthermore, we examined the effects of Src inhibition, p38-MAPK inhibition, and MAPK inhibition on NECA stimulated CREB phosphorylation in arterial smooth muscle to identify whether any of these kinases mediate NECA-induced CREB phosphorylation. It can be also understood and explored whether Src or p38 inhibition could affect stimulated NECA induced P38 signalling. Additionally, if PD98059 could prevent ERK phosphorylation was also tested. Therefore, through the chapter, it can be hypothesised that the activation of G coupled receptors (b2AR or A2BR) stimulates both CREB and P38 signalling in VSMC. It can be understood that GPCR and MAPK serve receptors that stimulate the production of cAMP and their downstream signalling to CREB and or p38. Further, this work will emphasize on understanding the importance of regulation of CREB and P38 in VMSC. 

References for P38 Signalling in VSMCs

*Hudson C, Kimura TE, Duggirala A, Sala-Newby GB, Newby AC, Bond M. Dual role of CREB in the regulation of VSMC proliferation: mode of activation determines pro-or anti-mitogenic function. Scientific reports. 2018 Mar 20;8(1):1-5.

** Klemm DJ, Watson PA, Frid MG, Dempsey EC, Schaack J, Colton LA, Nesterova A, Stenmark KR, Reusch JE. cAMP response element-binding protein content is a molecular determinant of smooth muscle cell proliferation and migration. Journal of Biological Chemistry. 2001 Dec 7;276(49):46132-41.

*** Koga Y, Tsurumaki H, Aoki-Saito H, Sato M, Yatomi M, Takehara K, Hisada T. Roles of cyclic AMP response element binding activation in the ERK1/2 and p38 MAPK signalling pathway in central nervous system, cardiovascular system, osteoclast differentiation and mucin and cytokine production. International journal of molecular sciences. 2019 Jan;20(6):1346.

****Nash CA, Brown LM, Malik S, Cheng X, Smrcka AV. Compartmentalized cyclic nucleotides have opposing effects on regulation of hypertrophic phospholipase Cε signaling in cardiac myocytes. Journal of molecular and cellular cardiology. 2018 Aug 1;121:51-9.

*****Nash CA, Wei W, Irannejad R, Smrcka AV. Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy. Elife. 2019 Aug 21;8: 48167.

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