Fast-Activating Voltage- and Calcium-Dependent Potassium (BK) Conductance Promotes Bursting in Pituitary Cells: A Dynamic Clamp Study

Abstract

The electrical activity pattern of endocrine pituitary cells regulates their basal secretion level. Rat somatotrophs and lactotrophs exhibit spontaneous bursting and have high basal levels of hormone secretion, while gonadotrophs exhibit spontaneous spiking and have low basal hormone secretion. It has been proposed that the difference in electrical activity between bursting somatotrophs and spiking gonadotrophs is due to the presence of large conductance potassium (BK) channels on somatotrophs but not on gonadotrophs. This is one example where the role of an ion channel type may be clearly established. We demonstrate here that BK channels indeed promote bursting activity in pituitary cells. Blocking BK channels in bursting lacto-somatotroph GH4C1 cells changes their firing activity to spiking, while further adding an artificial BK conductance via dynamic clamp restores bursting. Importantly, this burst-promoting effect requires a relatively fast BK activation/deactivation, as predicted by computational models. We also show that adding a fast activating BK conductance to spiking gonadotrophs converts the activity of these cells to bursting. Together, our results suggest that differences in BK channel expression may underlie the differences in electrical activity and basal hormone secretion levels among pituitary cell types and that the rapid rate of BK channel activation is key to its role in burst promotion.

Is bursting more effective than spiking in evoking pituitary hormone secretion? A spatiotemporal simulation study of calcium and granule dynamics

“…We have shown that bursting can be rescued by adding BK current back to the cell using the dynamic clamp technique (here and in Ref. 34). In Fig.…”

The relationship between two fast/slow analysis techniques for bursting oscillations

“…This prediction was tested experimentally and validated. 10 In summary, the different fast/slow decompositions tell us useful information about a model cell's dynamics, and with the dynamic clamp technique, often in combination with pharmacological agents, these model predictions can be and have been tested.…”

“…[6][7][8][9][10] Bursting activity is characterized by alternation between periods of spiking and periods of rest, and is driven by slow variations in one or more slowly changing variables, such as the intracellular calcium concentration. Bursting oscillations are often more efficient than tonic spiking in mediating the release of neurotransmitter or hormone.…”

The Molecular Cell Biology of Anterior Pituitary Cells

“…The reciprocal conversion is also true: addition of an artificial BK conductance to cultured gonadotrophs through the dynamic clamp technique changes their activity pattern from spiking to bursting. 19 Mathematical modeling predicted that the activation time constant of the BK conductance is important. BK activation must be fast to promote bursting; if too slow, then the BK current does not promote bursting and instead takes on its traditional inhibitory role on electrical activity.…”

“…BK activation must be fast to promote bursting; if too slow, then the BK current does not promote bursting and instead takes on its traditional inhibitory role on electrical activity. 19 Faster BK activation kinetics limit spike amplitude, preventing full activation of the repolarizing delayed rectifier K 1 current, so membrane potential weakly oscillates around a depolarized level 14,22,23 before falling back toward rest, which results in bursting, increased Ca 21 influx and global Ca 21 signals.…”