Abstract
The discovery of non-adrenergic, non-cholinergic neurotransmission in the gut and bladder in the early 1960's is described as well as the identification of adenosine 5'-triphosphate (ATP) as a transmitter in these nerves in the early 1970's. The concept of purinergic cotransmission was formulated in 1976 and it is now recognized that ATP is a cotransmitter in all nerves in the peripheral and central nervous systems. Two families of receptors to purines were recognized in 1978, P1 (adenosine) receptors and P2 receptors sensitive to ATP and adenosine diphosphate (ADP). Cloning of these receptors in the early 1990's was a turning point in the acceptance of the purinergic signalling hypothesis and there are currently 4 subtypes of P1 receptors, 7 subtypes of P2X ion channel receptors and 8 subtypes of G protein-coupled receptors. Both short-term purinergic signalling in neurotransmission, neuromodulation and neurosecretion and long-term (trophic) purinergic signalling of cell proliferation, differentiation, motility, death in development and regeneration are recognized. There is now much known about the mechanisms underlying ATP release and extracellular breakdown by ecto-nucleotidases. The recent emphasis on purinergic neuropathology is discussed, including changes in purinergic cotransmission in development and ageing and in bladder diseases and hypertension. The involvement of neuron-glial cell interactions in various diseases of the central nervous system, including neuropathic pain, trauma and ischemia, neurodegenerative diseases, neuropsychiatric disorders and epilepsy are also considered.
Highlights
The story really started when I took up my first postdoctoral post in Feldberg’s Department of Physiology at the National Institute for Medical Research
When Edith Bülbring, who led the leading smooth muscle laboratory in the UK, saw how useful this method was compared to the technical difficulties her group was facing with microelectrode recording from spontaneous smooth muscle of the guinea-pig taenia coli, her favourite preparation, she invited me to take up a postdoctoral position in the Department of Pharmacology, Oxford University
During a sabbatical leave visiting the laboratory of Che Su and John Bevan at UCLA, we were disconcerted to find adenosine 5'-triphosphate (ATP) release from NANC intrinsic inhibitory enteric neurons, and from sympathetic nerves supplying the taenia coli [11]
Summary
When Edith Bülbring, who led the leading smooth muscle laboratory in the UK, saw how useful this method was compared to the technical difficulties her group was facing with microelectrode recording from spontaneous smooth muscle of the guinea-pig taenia coli, her favourite preparation, she invited me to take up a postdoctoral position in the Department of Pharmacology, Oxford University. After a year in Ladd Prosser’s laboratory in Champaign-Urbana, IL, supported by a Rockefeller fellowship, I decided to take up a Senior Lectureship in the Department of Zoology in Melbourne in 1960, where after a short time I set up the sucrose-gap technique and began to build a research group. PhD student, we decided to stimulate the nerves supplying the smooth muscle of the guinea-pig taenia coli in the presence of atropine and bretylium to block cholinergic and adrenergic neurotransmission and expected to see depolarisation and contraction in response to direct stimulation of the muscle. I spent 6 months with Mike Rand at the School of Pharmacy in London to study details of the NANC inhibitory responses, for example, showing that they were present in intrinsic enteric neurons controlled by vagal or sacral parasympathetic nerves [5]
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