Presynaptic plasticity: The regulation of Ca2+-dependent transmitter release

Ba2+ replaces Ca2+/calmodulin in the activation of protein phosphatases and in exocytosis of all major transmitters

“…The inability of Ba 2÷ to activate calmodulin has been considered as an argument to question the true exocytotic nature of Ba2+-evoked release (see for discussion Robinson, 1992;McMahon and Nicholls, 1993;Verhage et al, 1995). However, the present results using calmodulin and phosphatase inhibition show that Ba 2÷ may act downstream of calmodulin activation: Ca 2+-and not Ba 2+-evoked release is blocked by a calmodulin antagonist, while both Ca 2+-and Ba2÷-evoked release are blocked by inhibition of phosphatase activity.…”

“…This lack of cellular components regulating the intracellular Ba 2÷ concentration and the limited size of a terminal (1 /xm diameter) will allow Ba 2÷ to accumulate and equilibrate rapidly within the terminal and evoke release, also in polarized nerve terminals (see also Tagliatela et al, 1989;Sihra et al, 1993). This equilibration of Ba 2÷ may be different from the subcellular Ca 2 ÷ distribution, which may show regional variations within the terminal (see for a review Verhage et al, 1995). It has been shown that the entrance of Ba 2+ into the terminal, potentially in concert with its inhibitory action on K + permeabilities, depolarizes the nerve terminal and hereby facilitates its own entrance through voltage-gated Ca 2+ channels (McMahon and Nicholls, 1993;Sihra et al, 1993).…”

“…Interestingly, whereas Ca 2 + requirements may differ for the release of different transmitters in a similar preparation (see Verhage et al, 1991bVerhage et al, , 1995, the effective concentration of Ba 2÷ was rather similar for different transmitters, whether they are released from small synaptic vesicles at the active zone or from large dense cored vesicles at more ectopic sites within the terminals. As discussed above, Ba 2+ may, in contrast to Ca 2+, equilibrate rapidly within the terminal.…”

“…In addition, the role of both ions in regulating protein phosphorylation and dephosphorylation was studied. Because different classes of transmitter appear to be regulated by different Ca 2+ concentrations and are released from different loci within the nerve terminal (Verhage et al, 1991 b), we have also compared representatives of all major classes of transmitter, i.e., the fast-acting amino acid transmitters which are released by high local Ca 2+ elevations from small synaptic vesicles at the active zone, neuropeptides which are released by small Ca 2+ elevations at ectopic sites within the terminal and catecholamines which may utilise both secretion pathways (see for a review Verhage et al, 1995).…”

Beyond the wiring diagram: signalling through complex neuromodulator networks

“…It is now clear that very many neurons-in some nervous systems, seemingly all neurons-release some complement of neuropeptides as cotransmitters alongside their 'primary' classical transmitter (Kupfermann 1991;Maggi 1995;Lundberg 1996;Hö kfelt et al 2000;Merighi 2002). Strikingly illustrating the cellbiological basis of the transmitter -modulator distinction, the large dense-core vesicles that contain the neuropeptides are typically segregated, even within the same synaptic terminals, away from the small clear vesicles that contain the classical transmitter (Merighi 2002;Salio et al 2006), to sites from which the neuropeptides are released more diffusely by smaller, slower elevations of intracellular Ca 2þ (Verhage et al 1994), so that the release of the neuropeptides and the classical transmitter can occur to some degree independently, for example in response to different firing patterns of the neuron. Altogether, it is the diversity of the neuropeptides that accounts for much of the modulator multiplicity in a system such as the crustacean STG (figure 1).…”