Connexin-made channels as pharmacological targets.
Gap junctions are clusters of intercellular channels that provide morphological support for direct diffusion of ions and low-molecular-weight molecules between adjacent coupled cells. Each gap junction channel is made by docking of two hemichannels or connexons, each formed by assembly of six proteins (connexins). 21 members of the connexin gene family are likely to be expressed in the human genome. These ubiquitous gated channels, allowing rapid intercellular communication and synchronisation of coupled cell activities, play critical roles in many signalling processes, including co-ordinated cardiac and smooth muscle contractions, neuronal excitability, neurotransmitter release, insulin secretion, epithelial electrolyte transport, etc. Mutational alterations in the connexin genes are associated with the occurrence of multiple pathologies, such as peripheral neuropathies, cardiovascular diseases, dermatological diseases, hereditary deafness and cataract. But the neuro- and cardioprotective effects of blocking agents of junctional channels show that closure of these channels may also be beneficial in certain pathological situations. Consequently, modulation of gap junctional intercellular communication is a potential pharmacological target. In contrast to most other membrane channels, no natural toxin or specific inhibitor of junctional channels has been identified yet and most uncoupling agents generally also affect other ionic channels and receptors. Future research, based for example on the recent developments in genetics, may clarify gap junction physiology. This will in turn provide promising perspectives for the development of targeted drugs.
Hervé
J-C
JC
Equipe "Interactions et Communications Cellulaires", Unité Mixte de Recherche CNRS n# 6187, Pôle Biologie-Santé, 40, avenue du R. Pineau, 86022 Poitiers, France. Jean.Claude.Herve@univ-poitiers.fr
Sarrouilhe
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D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D020126:Brefeldin A / Q000494:pharmacology; D017630:Connexins / Q000235:genetics / Q000502:physiology*; D017629:Gap Junctions / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D008969:Molecular Sequence Data; D008985:Monensin / Q000494:pharmacology
D000890:Anti-Infective Agents; D017630:Connexins; D007473:Ion Channels; D020126:Brefeldin A; D008985:Monensin