Role of β-Arrestin-2 in sodium taste processing

Signaling of G protein coupled receptors such as the angiotensin II type 1 receptor (AT1R) are regulated and mediated in part through the actions of arrestin proteins. Previously our team showed that mice with genetic deletion of β-arrestin-2 (ARRB2; Arrb2-NULL mice) exhibit exaggerated intake of sodium (Na), and this effect was paralleled in mice with conditional deletion of ARRB2 only from substructures of the brain. The objective of the current project was to further clarify the role of ARRB2 in Na ingestive behaviors. We hypothesized that Arrb2-NULL mice would exhibit increased intake of NaCl (saline) that satisfies the traditional definition of an “appetite” including behaviors indicating (i) specificity, (ii) increased motivation / drive to consume, and (iii) altered valence. Colonies of Arrb2-NULL mice (Jax: 011130) and C57BL/6 mice (Jax: 000664) were maintained at the Medical College of Wisconsin and supplied soy-free Inotiv 2920x diet (0.15% Na). First, licking to randomized solutions of sucrose (62.5-1000 mM), NaCl (75-1000 mM), citric acid (CA; 0.3-100 mM), or quinine (1-2000 μM) were evaluated during a brief-access paradigm (10 s trials) using a Davis Rig. Male Arrb2-NULL mice (n=11 vs 8 control) exhibited concentration-dependent elevated lick rates to sucrose (p< 0.001) and NaCl (p=0.002) but no change in licking behaviors toward water, CA, or quinine. Female Arrb2-NULL mice (n=8 vs 10 control) showed a similar exaggeration of licking to NaCl (p=0.002). Second, when the same cohort of mice were offered 150 mM NaCl versus water in a 2-bottle choice paradigm, Arrb2-NULL mice (n=12M+8F) exhibited increased (p< 0.05 for all) total fluid, saline, saline preference (M: 75 vs 54%; F: 74 vs 45%), and total Na intake relative to controls (n=8M+10F), and adulteration of both solutions by addition of quinine (125 μM for M; 2 μM for F) caused parallel reductions (p< 0.05) in all of these endpoints in all mice. After return to water vs. 150 mM NaCl, mice were then progressively shifted from 0.15% Na diet to customized versions with 0.3% or 1% Na, which caused further exaggerations in total fluid, saline, and total Na intakes (all p< 0.05) yet maintenance of an elevated saline preference in Arrb2-NULL mice. Third, in a naïve cohort, Arrb2-NULL mice (n=5M vs 7M control) exhibited a trend toward increased appetitive responses (mouth movement, lateral tongue protrusion, & paw licking; p=0.06) and significantly fewer aversive responses (gaping, forelimb flail, head shake, passive drip, & chin rub; p=0.04) in response to intraoral infusion of 100 μL of 150 mM NaCl over 60 s. Fourth, in another naïve cohort studied by 2-bottle choice assay (water vs 150 mM NaCl), the elevated total fluid, saline, total Na, and saline preference of Arrb2-NULL mice (n=7M) were abolished (all p< 0.05) by addition of the AT1R antagonist losartan (0.3 g/L) into both drink solutions, while these behaviors all returned immediately upon removal of the drug. Collectively, these findings indicate that the increased Na intake of Arrb2-NULL mice satisfies all of the characteristics of a canonically defined Na appetite and implicate the angiotensin AT1R in these effects. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.