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Osteoclasts are terminally differentiated, multinucleated cells specialized for bone resorption. Their systemic regulator, calcitonin, triggers morphometrically and pharmacologically distinct retraction (R) and quiescence (Q) effects on cell\u2010spread area and protrusion\u2013retraction motility, respectively, paralleling its inhibition of bone resorption. Q effects were reproduced by cholera toxin\u2010mediated G<jats:sub>s<\/jats:sub>\u2010protein activation known to increase [cAMP]<jats:sub>i<\/jats:sub>, unaccompanied by the [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> changes contrastingly associated with R effects. We explore a hypothesis implicating cAMP signaling involving guanine nucleotide\u2010exchange activation of the small GTPase Ras\u2010proximate\u20101 (Rap1) by exchange proteins directly activated by cAMP (Epac). Rap1 activates integrin clustering, cell adhesion to bone matrix, associated cytoskeletal modifications and signaling processes, and transmembrane transduction functions. Epac activation enhanced, whereas Epac inhibition or shRNA\u2010mediated knockdown compromised, the appearance of markers for osteoclast differentiation and motility following stimulation by receptor activator of nuclear factor kappa\u2010\u0392 ligand (RANKL). Deficiencies in talin and Rap1 compromised <jats:italic>in vivo<\/jats:italic> bone resorption, producing osteopetrotic phenotypes in genetically modified murine models. Translational implications of an Epac\u2010Rap1 signaling hypothesis in relationship to N\u2010bisphosphonate actions on prenylation and membrane localization of small GTPases are discussed.<\/jats:p>","DOI":"10.1111\/nyas.13861","type":"journal-article","created":{"date-parts":[[2018,5,30]],"date-time":"2018-05-30T09:56:26Z","timestamp":1527674186000},"page":"18-28","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Regulatory actions of 3\u2032,5\u2032\u2010cyclic adenosine monophosphate on osteoclast function: possible roles of Epac\u2010mediated signaling"],"prefix":"10.1111","volume":"1433","author":[{"given":"Kamalan","family":"Jeevaratnam","sequence":"first","affiliation":[{"name":"Faculty of Health and Medical Sciences University of Surrey  Guildford UK"},{"name":"School of Medicine Perdana University \u2013 Royal College of Surgeons Ireland  Selangor Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha C.","family":"Salvage","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Cambridge  Cambridge UK"},{"name":"Physiological Laboratory University of Cambridge  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengye","family":"Li","sequence":"additional","affiliation":[{"name":"Physiological Laboratory University of Cambridge  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher L.\u2010H.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Cambridge  Cambridge UK"},{"name":"Physiological Laboratory University of Cambridge  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,5,30]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1006\/scdb.1997.0221"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-185X.1993.tb00996.x"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.1993.sp003721"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1260473"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.1987.sp003084"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112584"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1464793103006262"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1320241"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.1993.sp003679"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00188348"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02555699"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(91)91345-D"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1993.1075"},{"key":"e_1_2_12_15_1","doi-asserted-by":"crossref","first-page":"3108","DOI":"10.1128\/iai.62.8.3108-3114.1994","article-title":"Pertussis toxin activates platelets through an interaction with platelet glycoprotein Ib","volume":"62","author":"Sindt K.A.","year":"1994","journal-title":"Infect. 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