Education

B.S., Biology with Honors, Morehouse College, Atlanta, GA, 1999
Ph.D., Neurobiology, David Geffen School of Medicine, UCLA, 2006
2nd year FIRST Postdoctoral Fellow, 2008 - present

Research Statement

Ca2+ influx through Cav1.3 L-type Ca2+ channels triggers the exocytosis of neurotransmitter from cochlear inner hair cells in response to acoustic stimuli.  Mice with genetic ablation of Cav1.3 are congenitally deaf, and exhibit pathological signs similar to human auditory neuropathies and synaptopathies.  Inner hair cells from these mice show abnormal connectivity with synaptic efferents and afferents, implicating Cav1.3 in the normal development and maintenance of hearing.  The essential role of Cav1.3 channels in auditory transmission suggests that Cav1.3 is a potential therapeutic target in treatments for hearing loss.  However, current L-type Ca2+ channel drugs do not distinguish between CaV1.3 and CaV1.2, another L-type Ca2+ channel that is ubiquitously expressed in the brain and heart, and so would have considerable side effects.  Thus, clarifying the physiological relevance and molecular mechanisms of Cav1.3 channel modulation in inner hair cells may facilitate the design of pharmaceuticals that are beneficial to hearing-impaired patients. 

Cav1.3 channels in cochlear inner hair cells may be linked to Usher Syndrome
USH1C is the genetic locus for the most severe form of Usher Syndrome, which causes combined deafness, blindness and vestibular problems in humans.  USH1C encodes for the PDZ-domain protein harmonin.  In addition to its, well reported, enrichment in apical hair bundles we have found that harmonin is present at synapses, the primary sites of Cav1.3 in inner hair cells.  We have shown that Cav1.3 channels interact with harmonin a1 subunits, PDZ interactions, and enhance voltage-dependent facilitation of current through the channel.  The “deaf-circler” mutation (dfcr) in harmonin produces the Usher Syndrome phenotype in mice.  dfcr mutant protein prevents physical and functional interactions of harmonin with recombinant Cav1.3 channels.  In addition, I have demonstrated that inner hair cells from dfcr mutant mice show impaired voltage-dependent facilitation and exocytosis.  Our results reveal a novel role for harmonin in supporting Cav1.3 Ca2+ currents and normal presynaptic function in IHCs.

Calcium binding proteins regulate inner hair cell Cav1.3 channels during the development of hearing
Cav1 channels undergo a negative feedback regulation known as inactivation, which depends on the Ca2+ binding protein calmodulin binding to the C-terminal domain of the a1-subunit.  Compared to in the heart, Cav1.3 currents in inner hair cells show weak inactivation.  Our lab has characterized a family of calmodulin-like Ca2+ binding proteins (CaBPs) that suppress inactivation by competing with calmodulin for interaction with Cav channels.  Published studies from our lab show that two CaBPs (CaBP1 and CaBP4) are highly expressed in inner hair cells.  Therefore, CaBPs are poised to compete with calmodulin for binding to Cav1.3.  I have demonstrated that, after the onset of hearing, inner hair cells show a shift in the level of inactivation.  However, inner hair cells from CaBP4 knockout do not exhibit this shift, highlighting a role for CaBP4 in the normal development of inner hair cell Ca2+ currents.  Ongoing experiments will determine the extent to which these age-dependent changes affect inner hair cell synaptic signaling.

Publications

Edmonds, B.W., Gregory, F.D., Schweizer, F.E. (2004) Evidence that fast exocytosis can be predominantly mediated by vesicles not docked at active zones in frog saccular hair cells.  J Physiol. 560(Pt 2):439-50.

Gregory, F.D., Schweizer, F.E. (2002) Exocytosis with a snap. Nat Neurosci. 5(1):4-6.

Emory University School of Medicine
Department of Pharmacology
Rollins Research Center, Room 5170
Atlanta, GA 30322
Tel: 404.712.8260
Fax: 404.727.0365
Email: fgregor@emory.edu