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

Adenosine 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 presynaptic 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.