Diagram shows structure and function of a typical intermediate-/small-conductance KCa3.1 channel. A single subunit (out of
four identical, forming a homotetramer) is depicted, with a pore region between transmembrane-spanning segments 5 and 6. A
rise of cytosolic Ca2+, resulting from agonist-mediated release of inositol 1,4,5-trisphosphate or Ca2+ influx from plasma membrane channels (receptor-operated, voltage-operated, transient receptor potential) increases KCa3.1
open probability via constitutively bound calmodulin (calmodulin C-domain [C-CaM], calmodulin N-domain [N-CaM]), hyperpolarizing
the cell. Subsequent Ca2+ influx creates a positive feedback, activating several signaling kinase cascades (extracellular signal–related kinase [ERK
1/2], p38-mitogen-activated protein kinase [MAPK], phosphatidylinositide 3 kinase [PI3K]/Akt, Smad2/3, mitogen-activated protein
kinase, etc.). Further downstream events include expression of monocyte chemoattractant protein-1, intracellular adhesion
molecule-1, plasminogen activator inhibitor, and several collagen isoforms, with resulting matrix deposition and fibrosis.
Channel expression and/or surface translocation are controlled by kinases and transcription factors as well (upper left). AP-1, activator protein 1; RTK, receptor-tyrosine kinase.