Evidence that M₁ muscarinic receptors enhance noradrenaline release in mouse atria by activating protein kinase C

Abstract

1 The Ml selective muscarinic agonist, McNeil A 343, enhanced the electrically evoked release of noradrenaline from postganglionic sympathetic nerves in mouse atria. This has been found previously to be due to activation of muscarinic receptors of the Ml subtype, probably located on sympathetic nerve terminals. The present study investigated the signal transduction mechanisms involved in the releaseenhancing effects of McNeil A 343. The release of noradrenaline from mouse atria was assessed by measuring the electrically-induced (3 Hz, 60 s) outflow of radioactivity from atria which had been pre-incubated with [3H]-noradrenaline.

M1 muscarinic receptor‐induced facilitation of ACh and noradrenaline release in the rat bladder is mediated by protein kinase C.

“…These results clearly indicate that PKA is not involved in the M1 facilitation of ACh release in the urinary bladder. This is consistent with the findings in mouse atrial preparation (Costa et al 1993). Another approach used to evaluate the role of PKC in Ml facilitation was to downregulate the enzyme by pretreating the bladder strips with a high concentration of a phorbol ester (PDB) which downregulates PKC in the cholinergic and adrenergic nerve terminals (Oda et al 1991).…”

“…Thus, it is reasonable to conclude that the effect of H-7 was mediated by an action on PKC and not on PKA. Second, the stable analogue of cAMP, 8-Br-cAMP, which activates PKA, did not alter ACh release but did increase the release of NA as reported earlier in mouse atrium (Costa et al 1993). These results clearly indicate that PKA is not involved in the M1 facilitation of ACh release in the urinary bladder.…”

“…PDB (5/M) was applied in the first 30 min of the washing period. As shown in the Table 2 (Costa et al 1993), on IS-evoked transmitter release was investigated using the two-stimulation protocol. When the drugs were administered 20 min before S2 they did not facilitate ACh release (P > 0-05 compared with control); however, they significantly (P < 0 05) increased the release of NA (P < 0 05).…”

“…(2) What signal transduction pathway is utilized by the M1 presynaptic facilitatory mechanisms in the bladder? Since previous studies revealed that both ACh and noradrenaline (NA) release in the central nervous system (Nichols, Haycock, Wang & Greengard, 1987;Allgaier et al 1988), as well as in the peripheral nervous system (Ishac & de Luca, 1988), are dependent upon the function of PKC and muscarinic receptors can activate PKC (Costa, Barrington & Majewski, 1993), the role of this second messenger pathway in Ml facilitation of ACh and NA release was evaluated.…”

Facilitation of transmitter release from rat sympathetic neurons via presynaptic P2Y1 receptors

“…However, this has also been found with other presynaptic Gq-linked receptors, for instance with M1 muscarinic cholinoceptors: on the one hand, M1 receptors mediate an enhancement of noradrenaline release from sympathetic nerve terminals through activation of PKC (Costa et al, 1993;Somogyi et al, 1996); on the other hand, these receptors mediate presynaptic inhibition through the depletion of membrane phosphatidylinositol 4,5-bisphosphate via PLC and the resulting closure of voltage-activated Ca 2+ channels (Kubista et al, 2009). As mentioned above, P2Y1 receptors have been reported to inhibit Kv7 channels as well as voltage-activated Ca 2+ channels in SCG neurons, and the latter effect is determined by the presence or absence of a scaffold protein (Filippov et al, 2010).…”