Extra-Cellular Proteins are Key Elements of a Global Molecular Network Enmeshing the Whole Central Nervous System: Physiological and Pathological Implications
Pp. 792-832 (41)
Guidolin Diego, Guescini Michele, Stocchi Vilberto, Genedani Susanna, Fuxe Kjell and Agnati L. Francesco
Proteins are endowed with the “Lego property”, i.e., the capability of steric
fitting with other proteins to form high molecular weight complexes with emergent
functions. These interactions may occur both as horizontal molecular networks at the
plasma membrane level and as vertical molecular networks, i.e., towards the extra- and/or
intracellular side of the cell. The present paper broadens this view by proposing the
existence of three dimensional molecular networks, mainly made by proteins and
carbohydrates, which might interact with each other at boundaries of compartments such as
plasma membranes to form a “global molecular network” (GMN) that pervades the intraas
well as the extra-cellular environment of the entire central nervous system. The GMN is
a potentially plastic structure regulated through several means. For example, its extracellular
part is under the remodeling action of the matrix metalloproteinases.
The proposal of a GMN has physiological and pathological implications.
In primis, classical synaptic transmission, gap junctions and volume transmission signals
by modulating GMN could importantly contribute to the “binding phenomenon”, i.e., the
phase synchronization of firing rates in far-located neuronal cortical groups.
Secondly, alterations in protein conformation could alter the GMN organization and
hence the neuronal network morphology and function. This could lead to the formation
of abnormal protein aggregates such as amyloid plaques and neurofibrillary tangles,
which, in turn, might affect the GMN function and/or the reciprocal interactions
between its parts especially at the boundaries between compartments.
Lego property, protein conformations, protein mosaics, protein-protein
interactions, allostery phenomenon, volume transmission, wiring transmission,
exosomes, microvesicles, lipid rafts, binding phenomenon, neurodegenerative
diseases, amyloid plaques, global molecular network, horizontal molecular network,
vertical molecular network, molecular interactions, central nervous system, matrix
metalloproteinases, extra-cellular space.
IRCCS San Camillo Lido, Venezia, Italy.