Ernest G. Peralta
In Memory of Ernie Peralta
With a long-standing interest in determining how muscarinic acetylcholine receptors modulate cardiac and smooth muscle function, exocrine secretion, and central neuronal activities important for learning and memory, Dr. Ernie Peralta pioneered the molecular studies that led the field into fascinating and uncharted territories. By his own account, Ernie was a reductionist whose approach to understanding a biological signaling pathway involved first identifying key molecular components of the system through gene cloning methods. These molecules were elegantly manipulated in "simple" heterologous expression systems with the aim of understanding how they interact to regulate interesting and fundamental physiological processes, such as neurotransmitter release at the synapse or pacemaker activity in the heart.
As a postdoctoral fellow at Genentech, Ernie helped to usher in a new and exciting era of molecular pharmacology by isolating cDNA clones encoding muscarinic acetylcholine receptors. Indeed, this work represents one of the earliest success stories in identifying a gene encoding a G protein-coupled receptor and examining its properties in heterologous expression systems. Ernie made great use of these clones by demonstrating that a single transmitter or hormone can modulate different second messenger signaling pathways, and that specificity is determined by the complement of receptor and G protein subtypes that a cell expresses. While this may seem obvious from today's perspective, Ernie's studies were among the first to establish a logical molecular framework for understanding how G protein-coupled receptors "talk" to specific G proteins and route their signals to a given second messenger signaling pathway.
Ernie's molecular analyses of the cloned muscarinic receptors revealed that inhibitory acetylcholine actions are mediated by the m2 and m4 receptors coupled to pertussis toxin-sensitive G proteins, whereas excitatory actions are mediated by m1, m3 and m5 receptors coupled to Gq/11 proteins and the phospholipase C pathway.
Following molecular characterization of the muscarinic acetylcholine receptors, Ernie's group went on to examine mechanisms underlying the inhibitory as well as the excitatory pathways. Their novel findings concerning the inhibitory pathways include molecular analysis of muscarinic potassium channel activation by the G protein beta-gamma subunits and biochemical studies of the function of the regulators of G protein signaling (RGS). In both cases, the studies were original and highly influential.
Of equal and perhaps even greater impact were the many discoveries of Ernie's group regarding mechanisms mediating the excitatory pathways. The unexpected finding of tyrosine kinase-mediated Kv1.2 potassium channel suppression by m1 receptor in neuroblastoma-glioma cells as well as expression systems received wide attention, pointing to connections between signaling pathways previously thought to be separate. Characteristic of Ernie's insightful and rigorous scientific style, his group pursued the underlying mechanisms to reveal a number of surprises. The uncovered novel effects of m1 receptor activation include ligand-independent EGF receptor activation, Pyk2 tyrosine kinase stimulation, Kv1.2 channel regulation via physical association with the small GTPase RhoA, and tyrosine phosphorylation-dependent association between the channel and receptor tyrosine phosphatase which in turn terminates channel suppression by m1 receptor.
In addition to the truly original and valuable leads that these studies have provided to the signaling field, the specific findings on m1 modulation of Kv1.2 channels will have major impact on our understanding of central nervous system functions. The Kv1.2 potassium channels are abundantly expressed in the mammalian brain. The m1 muscarinic acetylcholine receptor is known to increase neuronal excitability by inhibiting a number of potassium channels including the M channel. Despite intense interest and intensive studies for decades, however, how these various potassium channels in central neurons are modulated by acetylcholine remains unknown. The new paradigms established by studies of Peralta's group will provide important guides to future studies.
Ernie will be remembered as much for his open and gentle demeanor as for his substantial scientific achievements. Indeed, his personal and professional style to science was exemplary and he provided a heartening glimpse into what constructive and conscientious scientists can accomplish. He unselfishly shared his ideas with us and he gently critiqued ours. His help was without obligation. He created a laboratory environment that was both nurturing and supportive, and yet remained competitive and exciting. It was a wonderful place for a scientist to learn and grow. In his shortened career, Ernie mentored and trained many scientists. He remained active and intimately involved with their careers until his untimely death.
Ernie touched many of our lives. He was at once generous, inquisitive, insightful and helpful. Although these combined qualities are rare, Ernie showed us that they are not in conflict with success and fulfillment in the too frequently competitive and aggressive world of biomedical research. Ernie's warmth and bright presence in our community will be deeply missed by all of us, but his scientific and personnel legacy will remain as a wonderful source of strength and inspiration.
James D. Lechleiter, Ph.D. Associate Professor Department of Molecular Medicine Institute of Biotechnology University of Texas Health Science Center at San Antonio 15355 Lambda Drive San Antonio, TX 78245-3207