Potential roles of β3-adrenergic receptor in heart rate regulation via sinus node activity and local adipocyte metabolism.

β-Adrenergic signalling plays a central role in the regulation of diverse physiological processes, including cardiovascular function. In the heart, β1-adrenergic receptors (β1-ARs) mediate most sympathetic effects on contractility and heart rate, whereas the role of β3-ARs remains poorly understood. Here we investigated the expression and functional significance of β3-ARs in the sinus node (SN), the primary cardiac pacemaker. β3-AR expression showed a clear regional gradient, being highest in adipose tissue associated with the SN, modest in the SN itself, and minimal in atrial and ventricular myocardium. Single-nucleus RNA sequencing further demonstrated enriched β3-AR transcripts in adipocytes within the SN region and modest expression in SN and atrial myocytes. Pharmacological modulation of β3-AR activity influenced heart rate and altered spontaneous firing in isolated right atrial preparations containing the SN. These findings suggest that β3-AR signalling may influence pacemaker activity both directly within the SN and indirectly through local adipose tissue metabolism.