Mechanism of spontaneous and receptor-controlled electrical activity in pituitary somatotrophs: experiments and theory.
Cultured pituitary somatotrophs release growth hormone in response to spontaneous Ca(2+) entry through voltage-gated calcium channels (VGCCs) that is governed by plateau-bursting electrical activity and is regulated by several neurohormones, including GH-releasing hormone (GHRH) and somatostatin. Here we combine experiments and theory to clarify the mechanisms underlying spontaneous and receptor-controlled electrical activity. Experiments support a role of a Na(+)-conducting and tetrodotoxin-insensitive channel in controlling spontaneous and GHRH-stimulated pacemaking, the latter in a cAMP-dependent manner; an opposing role of spontaneously active inwardly rectifying K(+) (K(ir)) channels and G-protein-regulated K(ir) channels in somatostatin-mediated inhibition of pacemaking; as well as a role of VGCCs in spiking and large conductance (BK-type) Ca(2+)-activated K(+) channels in plateau bursting. The mathematical model is compatible with a wide variety of experimental data involving pharmacology and extracellular ion substitution and supports the importance of constitutively active tetrodotoxin-insensitive Na(+) and K(ir) channels in maintaining spontaneous pacemaking in pituitary somatotrophs. The model also suggests that these channels are involved in the up- and downregulation of electrical activity by GHRH and somatostatin. In the model, the plateau bursting is controlled by two functional populations of BK channels, characterized by distance from the VGCCs. The rapid activation of the proximal BK channels is critical for the establishment of the plateau, whereas slow recruitment of the distal BK channels terminates the plateau.
Tsaneva-Atanasova
Krasimira
K
Laboratory of Biological Modeling, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.
Sherman
Arthur
A
van Goor
Frederick
F
Stojilkovic
Stanko S
SS
D000818:Animals; D001683:Biological Clocks / Q000502:physiology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D003198:Computer Simulation; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D013007:Growth Hormone-Releasing Hormone / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology*; D008954:Models, Biological; D018408:Patch-Clamp Techniques / Q000379:methods; D010902:Pituitary Gland / Q000166:cytology* / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000502:physiology*; D012964:Sodium / Q000494:pharmacology; D013004:Somatostatin / Q000378:metabolism; D052683:Somatotrophs / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D013779:Tetrodotoxin / Q000494:pharmacology
D024681:Potassium Channels, Calcium-Activated; D011956:Receptors, Cell Surface; D013779:Tetrodotoxin; D013004:Somatostatin; D013007:Growth Hormone-Releasing Hormone; D012964:Sodium; D002118:Calcium