Connexin proteins share a common topology of four transmembrane alpha-helical domains, two extracellular loops, a cytoplasmic loop and cytoplasmic N- and C-termini. Many of the key functional differences arise from specific amino acid substitutions in the most highly conserved domains, the transmembrane and extracellular regions. Each of the approximately 20 connexin isoforms produces channels with distinct permeabilities and electrical and chemical sensitivities; therefore, one connexin usually cannot fully substitute for another. Consequently, a wide variety of malignant phenotypes associate with decreased connexin expression and gap junction communication, dependent on the particular connexin that is effected. For instance, downregulation of connexin 45 in the left ventricle associates with end-stage heart failure due both to ischaemic cardiomyopathy and idiopathic dilated cardiomyopathy.