The repeated evolution of tetrodotoxin (TTX) resistance provides a model for testing hypotheses about the mechanisms of convergent evolution. This poison is broadly employed as a potent antipredator defence, blocking voltage-gated sodium channels (Na v ) in muscles and nerves, paralysing and sometimes killing predators. Resistance in taxa bearing this neurotoxin and a few predators appears to come from convergent replacements in specific Na v residues that interact with TTX. This stereotyped

Beta-adrenoceptors start the most powerful signaling pathway for the sympathetic control of the cardiac function. Human and animal models of heart failure (HF), one of the most important causes of mortality worldwide, show alterations of the sympathetic system. Number and function of betaadrenoceptors, namely the beta-1 subtype, are impaired in HF, representing a major (mal)adaptive feature of myocardial remodeling. Moreover, HF is characterized by structural and functional remodeling of T-tubules (TT). We previously observed failure of action potential conduction in about 6% of HF TTs accompanied by profound alterations of local Ca 2þ transient (Crocini et al. PNAS 2014). Here, we employ an ultrafast random access multi-photon (RAMP) microscope to assess the effect of beta-adrenoceptor activation on Ca 2þ release in electrically coupled and uncoupled tubular elements. We find that HF cells exhibit a significantly higher Ca 2þ sparks frequency compared to controls that are not affected by beta-receptor activation (10-7 M isoproterenol). Control cardiomyocytes treated with isoproterenol show instead a more than 3-fold increase of Ca 2þ sparks frequency. To better examine this difference, we assess beta-adrenergic signaling role on Ca 2þ release. We observe an accelerated Ca 2þ rise exclusively in the vicinity of electrically coupled TT, while Ca 2þ rise close to failing elements is unchanged in beta-adrenergic stimulated cells. This finding indicates a patchy response of HF cells to beta-adrenergic stimulation. On the contrary, isoproterenol reduces the beat-to-beat variability of Ca 2þ release time to peak at every membrane site of HF cardiomyocytes. Simultaneous recording of action potential and Ca 2þ transient allows us to probe the effect of beta-adrenergic stimulation at subcellular level, disclosing specific local effects that may help understanding the changes of beta-adrenergic signaling in HF.

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