Update TRENDS in Endocrinology and Metabolism Vol.16 No.3 April 2005 83

relatively slow and requires Ca2C and CAPS, which bindsPtdIns(4,5)P2. The exact role of PtdIns(4,5)P2 binding inCAPS function is still not known, and the functionallyimportant PtdIns(4,5)P2 binding site on CAPS remains tobe identified. However, such Ca2C- and CAPS-dependentpriming only occurs if MgATP-dependent priming hasbeen completed. This model accommodates the desensi-tizing effects of sustained elevation in [Ca2C] on tonicsecretion in neuroendocrine cells, which could have a rolein depriming secretory vesicles.

Nagy et al. [12] also explored the molecular mechan-isms of vesicle priming and depriming, focusing on therole of SNAP25 in this process. They used phosphoryla-tion mutants of SNAP25 to show that protein kinase A(PKA)-dependent phosphorylation of SNAP25 increasesthe size of slowly and rapidly releasable secretory vesiclepools without affecting the kinetics of vesicle fusion,whereas calcineurin activity has the opposite effect.However, protein kinase C (PKC) activity and its phos-phorylation of SNAP25 regulate the refilling of pools afterthey are emptied. The authors further show the role of anadditional and still uncharacterized target of PKA thatparticipates in the control of priming. Their data alsoindicate that the rates of vesicle priming are not affectedby SNAP25 and other target-protein phosphorylation,which implies that the PKA signaling pathway affects therate of vesicle depriming. They also describe the potentialrole of differential splicing of SNAP25 (which exists in twoforms) in control of the vesicle-depriming rate. It appearsthat the baseline size of the releasable pools is determinedindependently by the particular splice variant of SNAP25,whereas phosphorylation by PKA regulates the relativesize of the exocytotic burst for both variants [13].

Summary

The overall message from these studies is that theintermolecular changes during the formation of the coretSNARE and trans-SNARE complexes occur in steps thatrequire a complex intracellular messenger milieu. Thefirst step in this process is the formation of a syntaxin–SNAP25 complex, which probably functions as a precursor

Corresponding author: Barkan, A.L. (abarkan@med.umich.edu).

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to the core complex formed during the Ca2C-dependentpriming step of exocytosis. It appears that cells have twoways of regulating SNAP25 functional contribution in thisprocess: alternative splicing and phosphorylation of thismolecule. In addition to SNAP25, CAPS also contributesto the priming of secretory vesicles. SNAP25 and CAPSnot only represent the qualitative elements of priming butalso influence the size of releasable vesicle pools, reflectingthe pre-translation and post-translation modification ofSNAP25 and regulation of PtdIns(4,5)P2, respectively.

References

1 Rettig, J. and Neher, E. (2002) Emerging roles of presynaptic proteinsin CaCC-triggered exocytosis. Science 298, 781–785

2 Martin, T.F. (2003) Tuning exocytosis for speed: fast and slow modes.Biochim. Biophys. Acta 1641, 157–165

3 DeCamili, P. and Jahn, R. (1990) Pathways to regulated exocytosis inneurons. Annu. Rev. Physiol. 52, 625–645

4 Sollner, T.H. (2003) Regulated exocytosis and SNARE function. Mol.Membr. Biol. 20, 209–220

5 Rothman, J.E. and Warren, G. (1994) Implications of the SNAREhypothesis for intracellular membrane topology and dynamics. Curr.Biol. 4, 220–223

6 Sollner, T.H. et al. (1993) SNAP receptors implicated in vesicletargeting and fusion. Nature 362, 318–324

7 Xu, T. et al. (1998) Multiple kinetic components of exocytosisdistinguished by neurotoxin sensitivity. Nat. Neurosci. 1, 192–200

8 An, S.J. and Almers, W. (2004) Tracking SNARE complex formation inlive endocrine cells. Science 306, 1042–1046

9 Dietrich, L.E.P. et al. (2003) Control of eukaryotic membrane fusion byN-terminal domains of SNARE proteins. Biochim. Biophys. Acta 1641,111–119

10 Walent, J.H. et al. (1992) A novel 145 kd brain cytosolic proteinreconstitutes Ca2C-regulated secretion in permeable neuroendocrinecells. Cell 70, 765–775

11 Grishanin, R.N. et al. (2004) CAPS acts at a prefusion step in dense-core vesicle exocytosis as a PIP2 binding protein. Neuron 43, 551–562

12 Nagy, G. et al. (2004) Regulation of releasable vesicle pool sizes byprotein kinase A-dependent phosphorylation of SNAP-25. Neuron 41,417–429

13 Nagy, G. et al. (2002) Protein kinase C-dependent phosphorylation ofsynaptosome-associated protein of 25 kDa at Ser187 potentiatesvesicle recruitment. J. Neurosci. 22, 9278–9286

1043-2760/$ - see front matter. Published by Elsevier Ltd.

doi:10.1016/j.tem.2005.02.002

Book Reviews

Everything you want to know about androgensTestosterone: Action, Deficiency, Substitution: Third Edition edited by Eberhard Nieschlag, Hermann M. Behre and

Susan Nieschlag, Cambridge University Press, 2004. US$130.00 (xiiiC747 pages) ISBN 0521833809

Ariel L. Barkan

Departments of Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan, Ann Arbor, MI 48109, USA

The third edition of the encyclopedic book Testosterone:Action, Deficiency, Substitution covers almost all aspectsof the general biology of androgens and their clinicalapplications. The authors are primarily from Europe but

the inclusion of contributors from the USA and Australiaensures an international flavor. This book includescomprehensive reviews of androgen biosynthesis, trans-port and molecular biology as well as two chapterscovering the molecular biology and clinical pathophysiol-ogy of androgen receptors. There are also overviews of thebiological actions of androgens on behavior, hair growth,

Update TRENDS in Endocrinology and Metabolism Vol.16 No.3 April 200584

bone and muscle metabolism, erythropoiesis, the cardio-vascular system and the prostate, and on the role ofandrogens in the initiation and maintenance of erection.Subsequent chapters provide well thought-out dis-cussions of the practical issues of androgen administrationfor the treatment of clinical hypogonadism, senescenceand non-gonadal disease and as a male contraceptive.The pharmacology of different androgen preparations,5-a-reductase inhibitors, dehydroepiandrosterone andandrostenedione and novel selective androgen receptormodulators is also discussed. In addition, there are twochapters covering the methodologies for detecting andro-gen abuse and for quantifying testosterone, dihydrotesto-sterone and sex-hormone-binding globulin. Every chapteris well written, relevant and timely.

Each chapter is generous in length (20–40 pages onaverage) and is followed by w150–300 references. Thisenabled the authors to conduct detailed discussions oftheir subjects without the fear of page limitations. Eachchapter also contains an ample number of relevant figuresand tables. Importantly, the list of references is unusuallycomprehensive and includes many articles published in2003. Having authored several book chapters myself, I

Corresponding author: Wu, S. (stephanie.wu@rosalindfranklin.edu).

www.sciencedirect.com

have experienced first-hand the frustrating delay betweenthe submission of chapters and the ultimate date ofpublication: the final list of references is usually outdatedby at least two to three years. To avoid this seeminglyinevitable outcome, the authors and editors met inSeptember 2003 to finalize the chapters and to ensurethat the references were up-to-date.

The organization of Testosterone is truly superb. Eachreview is subdivided into self-contained sub-chapters witha clear list of contents at the beginning and is concludedwith tabulated key messages given as 10–15 shortsentences. As a result, the book is easy to navigate andwill be useful to both seasoned endocrinologists and thosewho need a rapid introduction to the area.

I would strongly recommend Testosterone: Action,Deficiency, Substitution to all endocrinologists, basic andclinical alike, as an indispensable source of informationabout the fundamental biology and clinical physiology ofandrogens. The editors and the authors should becongratulated on their splendid achievement.

1043-2760/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.

doi:10.1016/j.tem.2005.02.008

An overview of the diabetic footDiabetic Foot: A Clinical Atlas by Sharad Pendsey, Martin Dunitz, 2003. US$99.95 (xvC218 pages) ISBN 184184425X

Stephanie Wu

Department of Surgery, Center for Lower Extremity Ambulatory Research (CLEAR), WilliamM. Scholl College of Podiatric Medicine,

Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA

Diabetes is thought by some clinicians to be the mostsignificant epidemic of our time. The World HealthOrganization (WHO) estimates that by 2030, 366 millionpeople will be diagnosed with this disease. Foot ulcera-tion is one of the most common severe complicationsassociated with diabetes. It is more prevalent thandiabetic retinopathy and end-stage renal disease, yetuntil recently the diabetic foot had not received muchattention. The foot has always been the forgotten childof medicine. It is an unglamorous part of the body towhich few healthcare providers and patients giveappropriate attention. For most it is difficult to imaginethat pathologies in this neglected part of the body couldbe so debilitating.

Pendsey’sDiabetic Foot is a succinct but comprehensiveoverview of diabetic foot ulceration. It gives readersinsight into the complex pathophysiology leading to theformation of diabetic foot ulceration and the debilitatingprogression to the final stages in which amputation isrequired. The book is easy to follow and includes morethan 600 clinical photographs and radiographs as well asmore than 50 case studies. The book is divided into eight

sections and consists of 48 chapters: each chapter containsan (often witty) key take-home point that conciselysummarizes the objective of the chapter. The book isunique in that the first two sections include chapters onthe gait cycle, the biomechanics of the foot, limited jointmobility, loss of intrinsic muscle function, structuraldeformation, and pathogenesis of ulcer formation, tohelp readers better understand why ulcerations occur inthe foot and why they have a predilection for certain areasof the foot. A basic understanding of the pathomechanicsbehind ulcer formation is fundamental for the preventionand treatment of diabetic foot ulcers and this is one of thefew books available that provides such comprehensivebackground information.

Pendsey has practiced in India for the past 20 years andseveral chapters (such as those on rat bites and lateralmalleolar bursitis in people who sit cross-legged) seemparticularly relevant to problems in India. However, thesechapters are short and add to the comprehensiveness ofthe book rather than being a distraction. In addition,Pendsey dedicated a section to prevention, emphasizingthe importance of patient education, preventive footwearand a multi-disciplinary approach in the management ofdiabetic foot ulcerations.