Purinergic signaling in diabetes and metabolism

Abstract

Purinergic signaling, a concept originally formulated by the late Geoffrey Burnstock (1929-2020), was found to modulate pathways in every physiological system. In metabolic disorders there is a role for both adenosine receptors and P2 (nucleotide) receptors, of which there are two classes, i.e. P2Y metabotropic and P2X ionotropic receptors. The individual roles of the 19 receptors encompassed by this family have been dissected - and in many cases the effects associated with specific cell types, including adipocytes, skeletal muscle, liver cells and immune cells. It is suggested that ligands selective for each of the four adenosine receptors (A₁, A_2A, A_2B and A₃), and several of the P2 subtypes (e.g. P2Y₆ or P2X7 antagonists) might have therapeutic potential for treating diabetes and obesity. This is a developing story with some conflicting conclusions relevant to drug discovery, which we summarize here.

Keywords: Adenosine receptors; Diabetes; Obesity; P2X receptors; P2Y receptors.

Figure 1.

Modulation of metabolic processes by adenosine signaling. Four adenosine receptors couple to G_i or G_s proteins and modulate the level of secondary messengers such as cAMP/Ca²⁺ to activate different signaling proteins. Metabolic processes regulated by adenosine receptors in liver, skeletal muscle, adipose tissue and pancreas. See Section 2 for details.

Figure 2.

Regulation of metabolically active tissues functions by P2Y and P2X receptors. Eight P2Y receptors are activated by receptor-specific nucleotide or nucleotide sugars. The receptors couple to different G-protein as indicated. Seven P2X receptors are membrane ion channels that are solely activated by ATP. Metabolic processes regulated by P2 receptors in liver, skeletal muscle, adipose tissue and pancreas. See Section 3 for details.