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Here, we developed a technology based on size exclusion to explore the function of \u03b2-ARs located in the OSM. We synthesized a PEG-Iso molecule by covalently linking isoprenaline (Iso) to a 5000 Da PolyEthylene-Glycol (PEG) chain to increase the size of the \u03b2-AR agonist and prevent it from accessing the T-tubule network. The affinity of PEG-Iso and Iso on \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    - and \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -ARs was measured using radioligand binding. Molecular dynamics simulation was used to assess PEG-Iso conformation and visualize the accessibility of the Iso moiety to water. Using confocal microscopy, we show that PEGylation constrains molecules outside the T-tubule network of adult rat ventricular myocytes (ARVMs) due to the presence of the extracellular glycocalyx. \u03b2-AR activation in OSM with PEG-Iso produced a lower stimulation of [cAMP]\n                    <jats:sub>i<\/jats:sub>\n                    than Iso but a larger stimulation of cytosolic PKA at equivalent levels of [cAMP]\n                    <jats:sub>I<\/jats:sub>\n                    and similar effects on excitation\u2013contraction coupling parameters. However, PEG-Iso produced a much lower stimulation of nuclear cAMP and PKA than Iso. Thus, OSM \u03b2-ARs in ARVMs control mainly cytosolic cAMP\/PKA pathway and contractility, while TTM \u03b2-ARs control mainly nuclear cAMP, PKA, and consequent nuclear protein phosphorylation. Size exclusion strategy using ligand PEGylation provides a unique approach to evaluate the respective contribution of T-tubule vs. OSM proteins in cardiac cells.\n                  <\/jats:p>","DOI":"10.7554\/elife.84243","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T09:15:08Z","timestamp":1758186908000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.84243","source":"Crossref","is-referenced-by-count":1,"title":["Distinct functions of cardiac \u03b2-adrenergic receptors in the T-tubule vs. outer surface membrane"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1409-133X","authenticated-orcid":true,"given":"George WP","family":"Madders","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xjwb503","id-type":"ROR","asserted-by":"publisher"}],"name":"Universit\u00e9 Paris-Saclay, Inserm, UMR-S 1180","place":["Orsay, 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