ω-Conotoxin GVIA-resistant neurotransmitter release from postganglionic sympathetic nerves in the guinea-pig vas deferens and its modulation by presynaptic receptors

1. Intracellular recording techniques were used to study neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals in the guinea-pig isolated vas deferens.
2. Recently, a component of action potential-evoked release which is insensitive to high concentrations of the selective N-type calcium channel blocker ω-conotoxin GVIA termed ‘residual release'' has been described. Under these conditions, release of the neurotransmitter ATP evoked by trains of low frequency stimuli is abolished, but at higher frequencies a substantial component of release is revealed.
3. ‘Residual release'' was studied with trains of 5 or 10 stimuli at stimulation frequencies of 10, 20 and 50 Hz. The α₂-adrenoceptor agonist clonidine (30–100 nM) inhibited ‘residual release'', the degree of inhibition being most marked at the beginning of a train.
4. The α₂-adrenoceptor antagonist yohimbine (1 μM) induced a marked increase in ‘residual release'' which was dependent on both the frequency of stimulation and the number of stimuli in a train.
5. Prostaglandin E₂ (30 nM) and neuropeptide Y (100 nM) caused a rapid inhibition of ‘residual release'' at all stimulation frequencies examined.
6. 4-Aminopyridine (100 μM) induced a powerful potential of ‘residual release'' and could reverse the inhibition of ω-conotoxin GVIA.
7. ‘Residual release'' was modulated through presynaptic α₂-adrenoceptors suggesting that (i) residual release of ATP is subject to α-autoinhibition through the co-release of noradrenaline, (ii) noradrenaline release can be triggered by calcium channels other than the N-type and (iii) when presynaptic receptors are activated, inhibition of transmitter release can occur by mechanisms other than modulation of calcium-entry through N-type calcium channels in postganglionic sympathetic nerves. Prostaglandin E₂ and neuropeptide Y also modulated neurotransmitter release.

     

Intrinsic regulation of locus coeruleus neurons: electrophysiological evidence indicating a predominant role for autoinhibition

Locus coeruleus neurons were antidromically activated and the resulting post-stimulation inhibition was compared to the interspike interval and examined for its dependency on antidromic invasion and stimulus intensity. The post-stimulation inhibition seen in these cells following antidromic activation approximated the interspike interval, was critically dependent on the antidromic invasion of the cell inder study and was only weakly dependent on stimulus intensity. These results suggest that the post-stimulation inhibition following antidromic activation in the locus coeruleus is mediated principally by autoinhibition and not by hypothesized local inhibitory interactions between locus coeruleus neurons.     

Autoinhibition and adapter function of Syk

Summary:  Development, survival, and activation of B lymphocytes are controlled by signals emanating from the B-cell antigen receptor (BCR). The BCR has an autonomous signaling function also known as tonic signaling that allows for long-term survival of B cells in the immune system. Upon binding of antigen to the BCR, the tonic signal is amplified and diversified, leading to alteration in gene expression and B-cell activation. The spleen tyrosine kinase (Syk) intimately cooperates with the signaling subunits of the BCR and plays a central role in the amplification and diversification of BCR signals. In this review, we discuss the molecular mechanisms by which Syk activity is inhibited and activated at the BCR. Importantly, Syk acts not only as a kinase that phosphorylates downstream substrates but also as an adapter that can bind to a diverse set of signaling proteins. Depending on its interactions and localization, Syk can signal opposing cell fate decisions such as proliferation or differentiation of B cells.