Aaron Fox, Ph.D.

Calcium channels and the regulation of secretion

Research Summary

Calcium ions entering cells through multiple types of voltage-dependent calcium channels regulate a variety of physiological processes including synaptic transmission, muscle contraction, regulation of calcium-dependent ion channels, regulation of calcium dependent enzymes etc. In addition to allowing a critical second messenger, calcium, to enter cells, calcium channels also play an important role in the generation of action potentials. Our lab studies the biophysical and pharmacological properties of various calcium channels and their regulation by neurotransmitters and second messengers. We also use molecular biological tools to isolate novel calcium channel subunits.

Of all the physiological properties regulated by calcium channels none is more important than the regulation of secretion that occurs at synapses or in secretory cells. Our lab studies secretion in both chromaffin and PC12 cells triggered by the activation of calcium channels. Furthermore, we study the proteins involved in the vesicle docking-fusion complexes, the sites where exocytosis occurs. Both exocytosis and endocytosis are being being studied in the lab. Our long-term goal is to prepare a quantitative model of secretion.

The weaver (wv) mouse disease is produced by the mutation of a single amino acid in a G-protein linked inwardly rectifying potassium channel, GIRK2. The substitution of a serine for a glycine, alters the pore-forming region of the potassium channel. The wv channels lose their selectivity for K⁺ ions; Na⁺ and Ca²⁺ ions permeate GIRK2wv channels. The result of the wv point mutation is cell death in the brain and testes. In the brain cerebellar granule cells die soon after birth as they fail to differentiate and migrate into the internal granule cell layer, which results in the prominent ataxia characteristic of these animals. Weaver mice also exhibit mild extrapyramidal locomotor abnormalities which are due to changes in dopaminergic transmission. There is a severe depletion of tyrosine hydroxylase positive neurons in the midbrain (substantia nigra, pars compacta) which is observed as early as the fourth post-natal week in weaver animals. Our lab is characterizing the permeability of wv channels to Na⁺ and Ca²⁺ and were exploring intracellular Ca²⁺ regulation in these animals. Interestingly, moving the wv gene into different strains of mice produces strikingly different diseases. Our lab is interested in finding out why these differences occur.

Selected Papers