Acidification of the intracellular space leads to closure of cardiac gap junction channels. It has been suggested that this process acts as one of the substrates for the generation of malignant ventricular arrhythmias consequent to myocardial ischemia. We have studied the molecular events that lead to pH-induced closure (“pH gating”) of channels formed by Connexin43 (Cx43), the most abundant cardiac gap junction protein. Our studies show that pH gating follows a particle-receptor model where the carboxyl terminal domain of Cx43, acting as a gating particle, binds to a region of the cytoplasmic loop, acting as a “receptor.” Additional studies, using nuclear magnetic resonance, have allowed us to characterize the secondary structures of the fragments involved and detect the amino acids that participate in the process. With this information at hand, we have used a high-throughput assay (phage display) to identify 12-mer peptidic sequences that can interfere with this particle-receptor interaction. A screening of an estimated 2.5 billion peptides led to the identification of a group of 48 sequences that can bind to the carboxyl terminal of Cx43. Through additional screenings, we singled out a particular peptide that can interfere with the regulation of Cx43 gap junctions by pHi. Studies currently in progress aim to determine the specific mechanism of action of this peptide and its potential use in cellular models of cardiac arrhythmias.