Abstract
The basic requirement for the transport of insulin-containing secretion granules towards the cell membrane and their fusion with the membrane is the elevation of intracellular concentration of calcium ions (Ca2+) in the b-cell. This is brought about by an increase in calcium transport into the cell via membrane voltage-gated calcium channels and ligand-gated Ca2+-channels of endoplasmic reticulum.
There are basically three mechanism acting: a) glucose, certain amino acids and fatty acids increase the ATP/ADP ratio in the b-cell, which causes the closure of ATP-dependent potassium channels (K+ATP), membrane depolarization and opening of Ca2+-channels in cell membrane; b) K+ATP channels can be also closed by sulphonylurea-like drugs; c) hormones (argvasopressin, glucagon, glucagon-like peptides (GLP-1,2), epinephrine, prolactin, growth hormone, etc) and neurotransmitters (acetylcholine, nitric oxide) influence the above-mentioned mechanisms by interacting with specific receptors. This leads to signal propogation by means of signal cascades including G-proteins, second messengers (cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP), diacylglycerol (DAG), inositol trisphosphate (IP3)/Ca2+), specific protein kinases (protein kinase A, C, G, tyrosine kinase cascades) and activation of effector molecules (ion channels, transcription factors, intracellular enzymes, etc).
The increase in intracellular calcium concentration affects the activity of at least two effector protein kinases: CaMK II (Ca2+/calmodulin-dependent kinase II) and MLCK (myosin light chain kinase). MLCK phosphorylates and thus activates myosin molecules in b-cell cytoplasm, which play an important role in secretion granule transport towards the cell membrane.
The role of CaMK II is still inadequately understood. The increasing amount of knowledge concerning the mechanisms underlying the insulin secretion from the b-cell provide us with possibilities to construct new pharmacological insulin secretagogues acting at different sites than drugs do today.