Impact of ectonucleotidases in autonomic nervous functions

• Membrane-bound ectonucleotidases regulate nucleotides (ATP, ADP, UTP, UDP) and adenosine levels at the cell surface.
• Distribution and enzymatic kinetics of ectonucleotidases in the ANS fine-tuning regulate P1 and P2 receptors activation.
• Ectonucleotidases cut-short activation of nucleotide-sensitive P2 receptors while favoring adenosine actions on P1 receptors.
• Desensitization of P2X1 and P2Y1 receptors in the ANS is prevented by ATP and ADP hydrolysis by ectonucleotidases.
• Pathophysiological alterations of ectonucleotidases in the ANS prompt for their use as potential pharmacological targets.

Adenine and uracil nucleotides play key functions in the autonomic nervous system (ANS). For instance, ATP acts as a neurotransmitter, co-transmitter and neuromodulator in the ANS. The purinergic system encompasses (1) receptors that respond to extracellular purines, which are designated as P1 and P2 purinoceptors, (2) purine release and uptake, and (3) a cascade of enzymes that regulate the concentration of purines near the cell surface. Ectonucleotidases and adenosine deaminase (ADA) are enzymes responsible for the hydrolysis of ATP (and other nucleotides such as ADP, UTP, UDP, AMP) and adenosine, respectively. Accordingly, these enzymes are expected to play an important role in the control of neuro-effector transmission in tissues innervated by both the sympathetic and parasympathetic divisions of the ANS. Indeed, ectonucleotidases have the ability to either terminate P2 receptor responses initiated by nucleoside triphosphates (ATP and UTP), and/or to favor the activation of ADP (e.g. P2Y1,12,13) and UDP (e.g. P2Y6) and/or adenosine (P1) specific receptors. In addition, ectonucleotidases can also importantly protect some P2 receptors from desensitization (e.g. P2X1, P2Y1). In this review, we present the (putative) roles of ectonucleotidases and ADA in the ANS with a focus on their regulatory activity at neuro-effector junctions in the following tissues: heart, vas deferens, urinary bladder, salivary glands, blood vessels and the intestine. We also present their implication in nociceptive transmission.