Timothy Angelotti MD, PhD

Research/Lab website:   Angelotti Lab Description

The sympathetic nervous system (SNS) functions as an integrative peripheral nervous system to regulate vital organ function, in part by release of norepinephrine (NE). Disease states as varied as Parkinson’s disease, spinal cord injury, diabetes, heart failure, and sepsis can all lead to dysfunction of the SNS and patient morbidity. Feedback modulation of NE release occurs by activation of alpha2A and alpha2C adrenergic receptors (ARs) on sympathetic neurons. Neuropharmacological differences between these two autoreceptors are not completely known, thus limiting development of specific drugs for disease treatment.


Modulation of sympathetic neuron signaling occurs by feedback inhibition of neurotransmitter release (autoreceptors), mediated in part via alpha2A and/or alpha2C adrenergic receptors. Previous research suggests that these two AR subtypes may have overlapping but unique physiological roles in neuronal signaling; however the basis for these differences is not completely known. Cellular localization is an important determinant of specialized function between homologous receptors. Preliminary data in cultured sympathetic ganglion neurons (SGN) and other cell types have found different temporal and spatial components to alpha2A&C AR localization and trafficking. These differences may relate to characteristics of SGN in culture (e.g. neurotransmitter phenotype) and thus may be important determinants of differential alpha2A&C AR modulation of neurotransmitter release. Using an array of molecular and cellular approaches and single cell amperometric analysis of neurotransmitter release, it should be possible to further delineate the interplay between protein structure, cellular localization, and physiological function of each receptor subtype. Resultant discoveries will be relevant to other similar neuromodulatory systems involved in pain and neural processing, including cannabinoid, opiate, and metabotropic glutamate receptors.