Neuronal and extraneuronal release of ATP and NAD⁺ in smooth muscle

Abstract

SUMMARYAdenosine 5′-triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD + ) are key intracellular constituents involved in energy transfer and redox homeostasis in the cell. ATP is also released in the extracellular space and in the past half century it has been assumed to be the purinergic neurotransmitter in many systems including smooth muscle. In some smooth muscles (i.e., the human urinary bladder detrusor muscle) ATP does appear to be primarily released from nerves upon action potential firings, but in other smooth muscles (i.e., the human large intestine) ATP does not mimic the endogenous purine neurotransmitter. It was recently found that NAD + , another ubiquitous intracellular adenine nucleotide, also follows a regulated release in neurosecretory cells, vascular and visceral smooth muscles, and the brain. In some cases NAD + fulfills pre-and postsynaptic criteria for a neurotransmitter better than ATP. Therefore, the purine hypothesis of neural regulation in smooth muscle is in need of reevaluation. This article will briefly review the current understanding of neuronal and extraneuronal release of purines in smooth muscle with emphasis on the roles of extracellular ATP and NAD + , and, further, will discuss more recent information about the likely involvement of multiple purines in smooth muscle neurotransmission.

Differential release of β‐NAD+ and ATP upon activation of enteric motor neurons in primate and murine colons

“…Just as the source of ATP is unknown, so is the mechanism responsible for ATP release in colon muscles. ATP can be released into the extracellular space via several mechanisms in addition to vesicle exocytosis, including connexin hemichannels, pannexin channels, ABC transporters, P2X7 receptor pores, and volume‐regulated channels 44–47 . We tested carbenoxolone, a blocker of connexin/pannexin channels, but this compound did not block the release of ATP.…”

Progress in understanding of inhibitory purinergic neuromuscular transmission in the gut

“…Identification of the purine derivative in purinergic vesicles may provide further evidence for the nature of the purinergic varicosities. According to a new model, β‐NAD [and perhaps, adenosine 5′‐diphosphate‐ribose (ADPR)] is contained in the purinergic vesicles in the enteric varicosities . However so far, β‐NAD has not been demonstrated in the enteric purinergic vesicles and no vesicular transporter of β‐NAD/ADPR has been identified.…”