J Physiol 588.24 (2010) p 4853 4853

PERSPECT IVES

CICR takes centre stage in β-cells:a cute cascade connects cAMP toCICR

Md. Shahidul IslamKarolinska Institutet, Departmentof Clinical Sciences and Education,Sodersjukhuset, 118 83 Stockholm, Swedenand Uppsala University Hospital,AR division, Uppsala, Sweden

Email: shahidul.islam@ki.se

An estimated 285 million people in theworld have overt β-cell failure, and thenumber is likely to increase to 438 millionby 2030 (Islam, 2010). Thus, under-standing the signalling mechanisms thatcontrol β-cell functions is a matter ofcrucial interest. Ca2+-induced Ca2+ release(CICR), first described in muscle cells,appears to be present in an increasingnumber of cell types. We now know thatCICR is neither restricted to the musclecells nor an exclusive property of theryanodine receptors (RyRs). In fact, boththe inositol 1,4,5-trisphosphate receptors(IP3Rs) and the RyRs can act as Ca2+-gatedCa2+ channels. CICR through IP3Rs issensitized by inositol 1,4,5-trisphosphate(IP3), whereas CICR through RyRs issensitized by a variety of small molecules,e.g. fructose 1,6-diphosphate (Kermodeet al. 1998) and arachidonic acid (Woolcottet al. 2006). In β-cells, CICR has takena two-decade-long journey from being

Figure 1. Schematic diagram showing the pathways whereby cAMP facilitates CICR inβ-cells

highly controversial to taking centre stage inrecent years. In fact, new therapeutic agentsthat facilitate CICR in β-cells, e.g. severalglucagon-like peptide 1 (GLP-1) analogues,are being increasingly used to improve β-cellfunction in diabetes. An understanding ofthe molecular mechanisms by which GLP-1facilitates CICR is thus also of clinicalrelevance.

GLP-1 facilitates CICR mainly byproducing cAMP, which acts through cyclicAMP-dependent protein kinase A (PKA).But, it turned out that activation of PKAcould not fully account for the facilitationof CICR by GLP-1. Another direct targetfor cAMP is a guanine nucleotide exchangefactor for the Ras-like small GTPase Rap(Epac). This factor is a product of twogenes, Epac1 and Epac2. Epac2 has twodomains for binding cAMP and a guaninenucleotide exchange factor for Ras-likesmall GTPases. In β-cells, activation ofEpac2 facilitates CICR. How does Epac2facilitate CICR? Oestreich et al. (2009) haveaddressed this question in heart musclecells where the critical importance of CICRis established beyond any doubt. In thisissue of The Journal of Physiology, Dzhuraet al. (2010) have addressed the samequestion in β-cells. Using pharmacologicalactivators of Epac, and Epac2 knockoutmice, these authors demonstrate again thatthis molecule does indeed play a distinctrole in facilitating CICR.

An unexpected finding of this study isthat β-cells express the phosphoinositide-specific phospholipase C ε (PLC-ε). Likeother PLCs, PLC-ε generates inositol

1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). In addition, it has bothRas guanine exchange factor (RasGEF)and Ras-associating (RA) domains. Thus,it acts as an activator and an effector ofsmall GTPases, like Ras and Rap. Eachmolecule of Epac2 binds to two moleculesof cAMP and the Epac2:cAMP complexactivates Rap1 (Fig. 1). The GTP-boundRap1 then binds to the RA domain ofPLC-ε and increases its phospholipaseactivity. Using PLC-ε knock-out mice,Dzhura et al. demonstrate that PLC-εis essential for the PKA-independentfacilitation of CICR by GLP-1. In a seriesof carefully designed experiments usingmolecular techniques and pharmacologicaltools, the authors demonstrate that theEpac2- and Rap1-mediated activationof PLC-ε facilitates CICR throughactivation of protein kinase C (PKC) andcalcium–calmodulin-dependent proteinkinase II (CaMKII) (Fig. 1).

Thus, CICR in β-cells is a highly regulatedprocess where cAMP plays an obligatoryrole. Facilitation of CICR by the two cAMPeffectors is also clearly discernable. It shouldbe pointed out that, in vitro, half-maximalactivation of PKA occurs at ∼1 μM

cAMP whereas half-maximal activation ofEpac2 (the B domain of Epac2) occurs at∼40 μM cAMP. One can speculate that thePKA-mediated facilitation of CICR occurswhen GLP-1 concentration is low, whereasEpac2-mediated facilitation of CICRoccurs during stimulation of the GLP-1Rby pharmacological concentrations ofGLP-1.

References

Dzhura I, Chepurny OG, Kelley GG, Leech CA,Roe MW, Dzhura E, Afshari P, Malik S,Rindler MJ, Xu X, Lu Y, Smrcka AV & HolzGG (2010). J Physiol 588, 4871–4889.

Islam MS (2010). Islets 2, 209.Kermode H, Chan WM, Williams AJ &

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BC, Kelley GG, Dirksen RT & Smrcka AV(2009). J Biol Chem 284, 1514–1522.

Woolcott OO, Gustafsson AJ, Dzabic M, PierroC, Tedeschi P, Sandgren J, Bari MR, Hoa NK,Bianchi M, Rakonjac M, Radmark O,Ostenson CG & Islam MS (2006). CellCalcium 39, 529–537.

C© 2010 The Author. Journal compilation C© 2010 The Physiological Society DOI: 10.1113/jphysiol.2010.202291