Modulation of Internal Calcium and Synaptic Function by Neurotransmitters 
Measurements of calcium transients in re- 
sponse to action potentials show that, in the ab- 
sence of 5-HT, dihydropyridines have a relatively 
small effect, reducing calcium entry by less than 
1 0 percent. Thus the lack of effect of dihydropyr- 
idines under normal conditions could simply be 
explained by their small contribution to total cal- 
cium influx. However, in the presence of 5-HT, 
application of dihydropyridines causes a substan- 
tial decrease in the amount of calcium influx, 
without affecting transmitter release. This leads 
us to conclude that the L-type calcium channels 
must be segregated from release sites. 
How much of the increase in the calcium 
transient with 5-HT is due to modulation of the 
L-type calcium channels and how much is due 
to the increased calcium influx via the N-type 
calcium channels as a consequence of the in- 
crease in action potential duration? To answer 
this question we compared the increase in the 
calcium transient in response to 5-HT in the ab- 
sence and presence of dihydropyridines. About 
two-thirds of the increase is due to the increase 
in the L current, while one-third is due to cal- 
cium influx via the N-type channels, which pre- 
sumably contribute to the increase in transmit- 
ter release. 
These results provide direct evidence in sup- 
port of the hypothesis that alterations in calcium 
influx at presynaptic terminals is involved in 
modulating the strength of synaptic transmission. 
However, the results also raise several questions 
currently under investigation. To what extent 
does the change in calcium account quantita- 
tively for the change in transmitter release? Can 
we visualize local clusters of L-type and N-type 
calcium channels and show that only the N-type 
channels are present at presynaptic release sites? 
To what extent are long-term changes in synaptic 
transmission due to changes in calcium entry? 
What role do the L-type channels play in cellular 
physiology? 
A. Control 
EOnm 
ICa-lj 
>149) nM — ■! 
994 -1108 nM — W 
643 - 751 nM — 
97- 195 nM — I 
rest 
a.p.s 
B. 5HT 
rest 
a.p.s 
Pseudocolor image of intracellular calcium 
concentration in a presynaptic process of an 
Aplysia sensory neuron. A: Left panel shows 
that, at rest, resting calcium is low. After stimu- 
lating a brief train of action potentials, there is 
a rise in intracellular calcium. 
B: After application of the facilitatory trans- 
mitter serotonin (5-HT), the same train of ac- 
tion potentials gives rise to a much larger in- 
crease in calcium. Scale applies to all panels. 
Research of Steven A. Siegelbaum. 
408 
