Data di Pubblicazione:
2015
Citazione:
HCN Channels : the Molecular Basis for their cAMP-TRIP8b Regulation / A.C. Saponaro, C. Donadoni, S.R. Pauleta, F. Cantini, M. Matzapetakis, G. Thiel, L. Banci, B. Santoro, A. Moroni. - In: BIOPHYSICAL JOURNAL. - ISSN 0006-3495. - 108:2 suppl. 1(2015 Jan 27), pp. 366A-366A. ((Intervento presentato al 59. convegno Biophysical Meeting tenutosi a Baltimore nel 2015 [10.1016/j.bpj.2014.11.2009].
Abstract:
Hyperpolarization-activated cyclic nucleotide-regulated (HCN1-4) channels
are involved in the regulation of several higher order neural functions, such
as short- and long-term memory processes (1). HCN channels are exquisitely
sensitive to endogenous levels of cAMP, since they directly bind cAMP
through a specialized domain in their cytoplasmic C-terminus (cyclic nucleotide
binding domain, CNBD) (2). In addition to cAMP, HCN channels are
further regulated by TRIP8b, their brain-specific auxiliary subunit. TRIP8b antagonizes
the effect of cAMP on HCN channel opening, as it interacts with the
CNBD of the channel (3). We employed solution NMR methodologies to determine
the 3D structure of the human HCN2 CNBD in the cAMP-free form, and
mapped on it the TRIP8b interaction site. Thus, we were able to reconstruct, for
the first time, the molecular mechanisms underlying the dual regulation of HCN
channel activity by cAMP-TRIP8b (4). Furthermore, site-directed mutagenesis
followed by biochemical/biophysical analysis allowed us to identify key residues
within the CNBD involved in TRIP8b binding. These new structural information
will provide deeper insights into the molecular basis of neurological
disorders associated with dysfunction of the HCN channel conductance in neurons,
potentially leading to the design of drugs able to modulate HCN channel
mediated memory processes.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
A.C. Saponaro, C. Donadoni, S.R. Pauleta, F. Cantini, M. Matzapetakis, G. Thiel, L. Banci, B. Santoro, A. Moroni
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