Modulation of Purinergic Neuromuscular Transmission by Phorbol Dibutyrate is Independent of Protein Kinase C in Murine Urinary Bladder

Searl, Timothy J; Silinsky, Eugene M.

doi:10.1124/jpet.112.194704

Cited by 3 publications

(6 citation statements)

References 49 publications

(49 reference statements)

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“…The authors raised the possibility that EJPs result from the activation of two different membrane conductances and that the variation in EJP amplitude may be related to the degree of coupling between smooth muscle cells in and between muscle bundles. EJPs, but not sEJPs, recorded in mouse bladder, were abolished by tetrodotoxin, but both EJPs and sEJPs were abolished by NF279, a P2X1 receptor antagonist [602]. The authors also showed that phorbol dibutyrate potentiated EJP amplitudes, but not those of sEJPs, probably by increasing ATP release from the nerve varicosities.…”

Section: Parasympathetic Cotransmissionmentioning

confidence: 51%

Purinergic signalling in the urinary tract in health and disease

Burnstock

2013

Purinergic Signalling

143

149

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Purinergic signalling is involved in a number of physiological and pathophysiological activities in the lower urinary tract. In the bladder of laboratory animals there is parasympathetic excitatory cotransmission with the purinergic and cholinergic components being approximately equal, acting via P2X1 and muscarinic receptors, respectively. Purinergic mechanosensory transduction occurs where ATP, released from urothelial cells during distension of bladder and ureter, acts on P2X3 and P2X2/3 receptors on suburothelial sensory nerves to initiate the voiding reflex, via low threshold fibres, and nociception, via high threshold fibres. In human bladder t h e p u r i n e rg i c c o m p o n e n t o f p a r a s y m p a t h e t i c cotransmission is less than 3 %, but in pathological conditions, such as interstitial cystitis, obstructed and neuropathic bladder, the purinergic component is increased to 40 %. Other pathological conditions of the bladder have been shown to involve purinoceptor-mediated activities, including multiple sclerosis, ischaemia, diabetes, cancer and bacterial infections. In the ureter, P2X7 receptors have been implicated in inflammation and fibrosis. Purinergic therapeutic strategies are being explored that hopefully will be developed and bring benefit and relief to many patients with urinary tract disorders.

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Section: Parasympathetic Cotransmissionmentioning

confidence: 51%

Purinergic signalling in the urinary tract in health and disease

Burnstock

2013

Purinergic Signalling

143

149

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“…In contrast with the human detrusor muscle, neurotransmission to murine detrusor muscle consists of both cholinergic and purinergic components (Searl and Silinsky, 2012a). Indeed, contractions in response to EFS (10 Hz, 5 seconds duration) were reduced to 63% 6 8% of the control after application of atropine (n 5 8), confirming that a substantial portion of the contractile response in the murine bladder is mediated by purinergic receptors.…”

Section: Resultsmentioning

confidence: 56%

“…The purinergic component of neurotransmission in the murine detrusor provides a means to measure both the purinergic component of neurotransmission and changes in postjunctional sensitivity to ATP by exploiting the electrically evoked EJP and spontaneous sEJP amplitudes (Searl and Silinsky, 2012a). As shown in Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Because neurotransmission in the murine detrusor muscle is mediated by both P2X purinoreceptors and muscarinic receptors (Searl and Silinsky, 2012a), the mouse detrusor represents a valuable tool for the study of P2X receptors. In addition, the presence of a P2X-mediated component of neurotransmission (P2X receptors are ligand-gated cation channels) allows the use of electrophysiological recording (Hoyle and Burnstock, 1985;Fujii, 1988;Brading and Mostwin, 1989;Bramich and Brading, 1996;2012a). Specifically, evoked responses measured as electrically evoked excitatory junctional potentials (EJPs) and spontaneous excitatory junctional potentials (sEJPs) can both be measured, thereby allowing quantal analysis of changes in neuromuscular transmission to be determined in murine detrusor preparations (Searl and Silinsky, 2012a).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the presence of a P2X-mediated component of neurotransmission (P2X receptors are ligand-gated cation channels) allows the use of electrophysiological recording (Hoyle and Burnstock, 1985;Fujii, 1988;Brading and Mostwin, 1989;Bramich and Brading, 1996;2012a). Specifically, evoked responses measured as electrically evoked excitatory junctional potentials (EJPs) and spontaneous excitatory junctional potentials (sEJPs) can both be measured, thereby allowing quantal analysis of changes in neuromuscular transmission to be determined in murine detrusor preparations (Searl and Silinsky, 2012a). This electrophysiological approach has proven useful in the past to enhance our understanding of the cellular mechanisms underlying neuromuscular modulation (Silinsky, 2004) and can be used to facilitate the examination of the mechanisms regulating parasympathetic transmission in the mammalian bladder (Searl and Silinsky, 2012a).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A1 Adenosine Receptor-Mediated Inhibition of Parasympathetic Neuromuscular Transmission in Human and Murine Urinary Bladder

Searl

Dynda

Alanee

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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The potential role of A 1 adenosine receptors in modulating neuromuscular transmission in the detrusor muscle of the urinary bladder has been tested in human and murine preparations with the intent to determine the viability of using adenosine receptor agonists as adjuncts to treat overactive bladder. In human detrusor muscle preparations, contractile responses to electrical field stimulation were inhibited by the selective A 1 adenosine receptor agonists 2-chloro-N the effects of CPA, thus confirming the role of A 1 receptors in human detrusor preparations. In murine detrusor muscle preparations, contractions evoked by electrical field stimulation were reduced by CPA or adenosine. Amplitudes of the P2X purinoceptor-mediated excitatory junctional potentials (EJPs) recorded with intracellular microelectrodes were reduced in amplitude by CPA and adenosine with no effect on the spontaneous EJP amplitudes, confirming the prejunctional action of these agents. 8-Cyclopentyltheophylline, a selective A 1 receptor antagonist, reversed the effects of CPA on EJP amplitudes with no effect of spontaneous EJPs, confirming the role of A 1 receptors in mediating these effects.

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Selective reduction of neurotransmitter release by cAMP-dependent pathways in mouse detrusor

Chakrabarty

Drake

Fry

2022

American Journal of Physiology-Regulatory, Integrative and Comp

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Parasympathetic nerve-mediated contractions of detrusor smooth muscle are generated by ATP and ACh release from efferent nerve terminals. In humans, ACh is responsible for detrusor contractions in normal human bladders, whereas ATP has an additional role in overactive bladder pathologies. The ATP metabolite, adenosine, relaxes nerve-mediated contractions, with a potential action via presynaptic adenosine A1 receptor activation and subsequent suppression of neuronal ATP release. We investigated the effect of A1 receptor activation and downstream cAMP-dependent pathways on nerve-mediated ATP and ACh release, and detrusor contraction in mouse detrusor. Bladders from male C57BL/6 mice (12 weeks) were used. Upon electrical field stimulation of intact preparations (detrusor and mucosal layers), ATP or ACh release was measured simultaneously with tension recordings. Activation of A1 receptors by adenosine or exogenous agonists reduced the lower frequency component of nerve-mediated contractions, and neuronal ATP release. The A1 receptor antagonist abolished these effects. A1 receptor activation inhibits AC activity and cAMP generation. The effect of A1 receptor activation was mimicked by a PKA antagonist, but not by modulators of exchange proteins activated by cAMP, demonstrating that modulation of nerve-mediated ATP release is via PKA. Adenosine had no effect on ACh release or the higher frequency component of nerve-mediated contractions. Differential regulation of neurotransmitter release is possible at the detrusor nerve-muscle junction, as demonstrated by A1 receptor activation, and downstream inhibition of AC, cAMP generation and PKA. The ability to specifically attenuate ATP release offers a potential to target purinergic motor pathways enhanced in overactive bladder pathologies.

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Modulation of Purinergic Neuromuscular Transmission by Phorbol Dibutyrate is Independent of Protein Kinase C in Murine Urinary Bladder

Cited by 3 publications

References 49 publications

Purinergic signalling in the urinary tract in health and disease

Purinergic signalling in the urinary tract in health and disease

A1 Adenosine Receptor-Mediated Inhibition of Parasympathetic Neuromuscular Transmission in Human and Murine Urinary Bladder

Selective reduction of neurotransmitter release by cAMP-dependent pathways in mouse detrusor

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