Connexin channel permeability to cytoplasmic molecules

Abstract

Connexin channels are known to be permeable to a variety of cytoplasmic molecules. The first observation of second messenger junctional permeability, made ∼30 years ago, sparked broad interest in gap junction channels as mediators of intercellular molecular signaling. Since then, much has been learned about the diversity of connexin channels with regard to isoform diversity, tissue and developmental distribution, modes of channel regulation, assembly and expression, biochemical modification and permeability, all of which appear to be dynamically regulated. This information has expanded the potential roles of connexin channels in development, physiology and disease, and made their elucidation much more complex -30 years ago such an orchestra of junctional dynamics was unanticipated. Only recently, however, have investigators been able to directly address, in this more complex framework, the key issue: What specific biological molecules, second messengers and others, are able to permeate the various types of connexin channels, and how well? An important related issue, given the ever-growing list of connexin-related pathologies, is how these permeabilities are altered by disease-causing connexin mutations. Together, many studies show that a variety of cytoplasmic molecules can permeate the different types of connexin channels. A few studies reveal differences in permeation by different molecules through a particular type of connexin channel, and differences in permeation by a particular molecule through different types of connexin channels. This article describes and evaluates the various methods used to obtain these data, presents an annotated compilation of the results, and discusses the findings in the context of what can be inferred about mechanism of selectivity and potential relevance to signaling. The data strongly suggest that highly specific interactions take place between connexin pores and specific biological molecular permeants, and that those interactions determine which cytoplasmic molecules can permeate and how well. At this time, the nature of those interactions is unclear. One hopes that with more detailed permeability and structural information, the specific molecular mechanisms of the selectivity can be elucidated.

Connexin43 Potentiates Osteoblast Responsiveness to Fibroblast Growth Factor 2 via a Protein Kinase C-Delta/Runx2–dependent Mechanism

“…Depending on the connexin subunits that make up a gap junction channel, gap junctions have varying size and charge permeability characteristics (Goldberg et al, 2004;Weber et al, 2004). Gap junctions formed by Cx43 have among the largest pore diameter, permitting the diffusion of molecules up to 1.2 kDa, with permeability preferences for molecules that are negatively charged (Weber et al, 2004;Harris, 2007). The second messengers produced in response to FGFR activation, IP3, DAG, calcium and arachidonic acid, are all small enough to theoretically pass through Cx43 channels.…”

GJA1mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype

“…Most cell types express multiple connexin isoforms, allowing for variability of gap junction composition and therefore its channel properties. Single channel (unitary) conductance [Veenstra et al, 1994;Verselis and Veenstra, 2000;Kreuzberg et al, 2005], charge selectivity [Veenstra et al, 1995], pore size [Harris, 2007], and molecular permeabilities depend upon the connexin composition of the gap junction and are influenced by pH, connexin phosphorylation, and interacting proteins [Herve et al, 2007]. .…”

Identification of rab20 as a Potential Regulator of Connexin43 Trafficking

“…Gap junction proteins (connexins) provide a conduit for intercellular communication by forming channels that enable the diffusion of cytoplasmic ions and small molecules between cells in direct contact (Goldberg et al 2004;Harris 2007;Saez et al 2003). An emerging theme in the study of connexins is that formation of gap junction channels is a regulated process (Koval 2006;Laird 2006).…”