title: Age-related homeostatic midchannel proteolysis of neuronal L-type voltage-gated Ca²⁺ channels.
abstract: Neural circuitry and brain activity depend critically on proper function of voltage-gated calcium channels (VGCCs), whose activity must be tightly controlled. We show that the main body of the pore-forming α1 subunit of neuronal L-type VGCCs, Cav1.2, is proteolytically cleaved, resulting in Cav1.2 fragment channels that separate but remain on the plasma membrane. This "midchannel" proteolysis is regulated by channel activity, involves the Ca(2+)-dependent protease calpain and the ubiquitin-proteasome system, and causes attenuation and biophysical alterations of VGCC currents. Recombinant Cav1.2 fragment channels mimicking the products of midchannel proteolysis do not form active channels on their own but, when properly paired, produce currents with distinct biophysical properties. Midchannel proteolysis increases dramatically with age and can be attenuated with an L-type VGCC blocker in vivo. Midchannel proteolysis represents a novel form of homeostatic negative-feedback processing of VGCCs that could profoundly affect neuronal excitability, neurotransmission, neuroprotection, and calcium signaling in physiological and disease states.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Ioannis E
authors.initials: IE
authors.lastname: Michailidis
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Abele-Henckels
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Wei K
authors.initials: WK
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Bochao
authors.initials: B
authors.lastname: Lin
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Geyman
authors.affiliation: Neuroscience Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ehlers
authors.affiliation: Department of Statistics, Columbia University, New York, NY 10027, USA.
authors.forename: Eftychios A
authors.initials: EA
authors.lastname: Pnevmatikakis
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China. Electronic address: jy160@columbia.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
mesh_terms: D000367:Age Factors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D009474:Neurons / Q000378:metabolism*; D059748:Proteolysis; D051381:Rats; D014981:Xenopus
chemical_list: D020746:Calcium Channels, L-Type; D002118:Calcium