My main research interest is calcium signaling. Ionized free calcium (Ca²⁺) is important in regulating diverse cellular functions and serves as the critical link between a variety of physiological stimuli and their intracellular effectors. Specialized functions of Ca²⁺ in the nervous system include control of neurotransmitter release, membrane excitability and gene expression.

Since Ca²⁺ produces many of its intracellular effects by interacting with Ca²⁺ binding proteins according to bimolecular reaction kinetics, the ultimate effect of Ca²⁺ entry (e.g. through voltage-gated Ca²⁺ channels in the plasma membrane that open in response to membrane depolarization during an action potential or synaptic transmission) depends on the dynamics of the intracellular free Ca²⁺ concentration [Ca²⁺]. One of the main goals of my research is to understand the determinants of [Ca²⁺] dynamics and their modulation. This is interesting, and challenging, given the presence of intracellular compartments, such as mitochondria and the endoplasmic reticulum, that are endowed with specialized Ca²⁺ transport systems that permit them to either accumulate or release Ca²⁺ in a highly regulated manner.

Understanding Ca²⁺ signaling thus requires information about the changes in [Ca²⁺]_i that occur within these compartments during stimulation and the specialized Ca²⁺ transport pathways (channels, pumps and exchangers) that are responsible for these changes. To obtain this information, a number of complementary experimental methods are employed, including the patch clamp technique to monitor Ca²⁺ movements across the plasma membrane under voltage-clamp, and variety of fluorescent Ca²⁺ indicators to monitor [Ca²⁺]_i within different intracellular compartments and the spatial heterogeneity of [Ca²⁺]_i within individual compartments as they occur during and after stimulation.

Another focus of our research is to understand how Ca²⁺ regulatory dysfunction contributes to disease. We are currently studying how mutations in voltage-sensitive Ca²⁺ channels (VSCCs) lead to neurodegeneration, using mouse cerebellar Purkinje neurons as a model system. Previous studies have shown that mutations in P/Q-type VSCCs lead to Purkinje cell loss, but the mechanism linking the Ca²⁺ channel defect to cell death is unknown. Mutations in the same channel subtype are responsible for several forms of inherited diseases in humans (e.g. familial hemiplegic migraine, episodic ataxia type-2, and spinocerebellar ataxia type 6) so the results of our studies are expected to contribute to an understanding of how Ca²⁺ regulatory dysfunction contributes to human genetic disease.

1. Patterson M, Sneyd J, Friel DD. (2007)
   Depolarization-induced calcium responses in sympathetic neurons: relative contributions from Ca2+ entry, extrusion, ER/mitochondrial Ca2+ uptake and release, and Ca2+ buffering. J Gen Physiol. 2007 Jan 1; 129(1):29-56.
   Abstract Full PDF
2. Jones SW, Friel DD. (2006)
   The amplitude distribution of release events through a fusion pore. Biophys J. 2006 Mar 1; 90(5):L39-L41. 2006/01/13 [aheadofprint].
   Abstract Full PDF
3. Albrecht MA, Colegrove SL, Friel DD. (2002)
   Differential regulation of ER Ca²⁺ uptake and release rates accounts for multiple modes of Ca²⁺-induced Ca²⁺ release. J Gen Physiol. 2002 Mar; 119(3):211-233.
   Abstract Full PDF
4. Albrecht MA, Colegrove SL, Hongpaisan J, Pivovarova NB, Andrews SB, Friel DD. (2001)
   Multiple modes of calcium-induced calcium release in sympathetic neurons I: attenuation of endoplasmic reticulum Ca²⁺ accumulation at low [Ca²⁺]_i during weak depolarization. J Gen Physiol. 2001 Jul; 118(1):83-100.
   Abstract Full PDF
5. Hongpaisan J, Pivovarova NB, Colegrove SL, Leapman RD, Friel DD, Andrews SB. (2001)
   Multiple modes of calcium-induced calcium release in sympathetic neurons II: a [Ca2+](i)- and location-dependent transition from endoplasmic reticulum Ca accumulation to net Ca release. J Gen Physiol. 2001 Jul; 118(1):101-112.
   Abstract Full PDF
6. Friel DD. (2000)
   Mitochondria as regulators of stimulus-evoked calcium signals in neurons. Cell Calcium. 2000 Nov-Dec; 28(5-6):307-316.
   
7. Colegrove SL, Albrecht MA, Friel DD. (2000)
   Quantitative analysis of mitochondrial Ca2+ uptake and release pathways in sympathetic neurons. Reconstruction of the recovery after depolarization-evoked [Ca2+]i elevations. J Gen Physiol. 2000 Mar; 115(3):371-388.
   
8. Colegrove SL, Albrecht MA, Friel DD. (2000)
   Dissection of mitochondrial Ca2+ uptake and release fluxes in situ after depolarization-evoked [Ca2+](i) elevations in sympathetic neurons. J Gen Physiol. 2000 Mar; 115(3):351-370.
   
9. Friel DD. (1996)
   TRP: its role in phototransduction and store-operated Ca2+ entry. Cell. 1996 May 31; 85(5):617-619.
   
10. Friel DD. (1995)
    [Ca2+]i oscillations in sympathetic neurons: an experimental test of a theoretical model. Biophys J. 1995 May; 68(5):1752-1766.
    
11. Friel DD. (1995)
    Calcium oscillations in neurons. Ciba Found Symp. 1995; 188:210-23; discussion 223.
    

1. Friel, DD. (2003)
   Mitochondrial and ER-calcium uptake and release fluxes and their interplay in intact nerve cells. In: Understanding Calcium Dynamics, Lecture Notes in Physics. Eds. M. Falcke, H. Malchow. Springer, Berlin. 623:37-65.
   PDF
2. Friel, DD. (2000)
   Mitochondria as regulators of stimulus-evoked calcium signals in neurons. Cell Calcium. 28:307-316.
   Abstract
3. Friel, DD. (1995)
   [Ca²⁺]_i Oscillations in neurons. In: Ciba Symposium No. 188: [Ca²⁺]_i waves, gradients and oscillations. Wiley, Chichester.
   Abstract